Singh N

References (77)

Title : Design, Synthesis, and Biological Investigation of Quinazoline Derivatives as Multitargeting Therapeutics in Alzheimer's Disease Therapy - Verma_2024_ACS.Chem.Neurosci__
Author(s) : Verma A , Waiker DK , Singh N , Roy A , Saraf P , Bhardwaj B , Krishnamurthy S , Trigun SK , Shrivastava SK
Ref : ACS Chem Neurosci , : , 2024
Abstract : An efficient and promising method of treating complex neurodegenerative diseases like Alzheimer's disease (AD) is the multitarget-directed approach. Here in this work, a series of quinazoline derivatives (AV-1 to AV-21) were rationally designed, synthesized, and biologically evaluated as multitargeted directed ligands against human cholinesterase (hChE) and human beta-secretase (hBACE-1) that exhibit moderate to good inhibitory effects. Compounds AV-1, AV-2, and AV-3 from the series demonstrated balanced and significant inhibition against these targets. These compounds also displayed excellent blood-brain barrier permeability via the PAMPA-BBB assay. Compound AV-2 significantly displaced propidium iodide (PI) from the acetylcholinesterase-peripheral anionic site (AChE-PAS) and was found to be non-neurotoxic at the maximum tested concentration (80 microM) against differentiated SH-SY5Y cell lines. Compound AV-2 also prevented AChE- and self-induced Abeta aggregation in the thioflavin T assay. Additionally, compound AV-2 significantly ameliorated scopolamine and Abeta-induced cognitive impairments in the in vivo behavioral Y-maze and Morris water maze studies, respectively. The ex vivo and biochemical analysis further revealed good hippocampal AChE inhibition and the antioxidant potential of the compound AV-2. Western blot and immunohistochemical (IHC) analysis of hippocampal brain revealed reduced Abeta, BACE-1, APP/Abeta, and Tau molecular protein expressions levels. The pharmacokinetic analysis of compound AV-2 demonstrated significant oral absorption with good bioavailability. The in silico molecular modeling studies of lead compound AV-2 moreover demonstrated a reasonable binding profile with AChE and BACE-1 enzymes and stable ligand-protein complexes throughout the 100 ns run. Compound AV-2 can be regarded as the lead candidate and could be explored more for AD therapy.
ESTHER : Verma_2024_ACS.Chem.Neurosci__
PubMedSearch : Verma_2024_ACS.Chem.Neurosci__
PubMedID: 38327209

Title : Lead optimization based design, synthesis, and pharmacological evaluation of quinazoline derivatives as multi-targeting agents for Alzheimer's disease treatment - Verma_2024_Eur.J.Med.Chem_271_116450
Author(s) : Verma A , Waiker DK , Singh N , Singh A , Saraf P , Bhardwaj B , Kumar P , Krishnamurthy S , Srikrishna S , Shrivastava SK
Ref : Eur Journal of Medicinal Chemistry , 271 :116450 , 2024
Abstract : The complexity and multifaceted nature of Alzheimer's disease (AD) have driven us to further explore quinazoline scaffolds as multi-targeting agents for AD treatment. The lead optimization strategy was utilized in designing of new series of derivatives (AK-1 to AK-14) followed by synthesis, characterization, and pharmacological evaluation against human cholinesterase's (hChE) and beta-secretase (hBACE-1) enzymes. Amongst them, compounds AK-1, AK-2, and AK-3 showed good and significant inhibitory activity against both hAChE and hBACE-1 enzymes with favorable permeation across the blood-brain barrier. The most active compound AK-2 revealed significant propidium iodide (PI) displacement from the AChE-PAS region and was non-neurotoxic against SH-SY5Y cell lines. The lead molecule (AK-2) also showed Abeta aggregation inhibition in a self- and AChE-induced Abeta aggregation, Thioflavin-T assay. Further, compound AK-2 significantly ameliorated Abeta-induced cognitive deficits in the Abeta-induced Morris water maze rat model and demonstrated a significant rescue in eye phenotype in the A-phenotypic drosophila model of AD. Ex-vivo immunohistochemistry (IHC) analysis on hippocampal rat brains showed reduced Abeta and BACE-1 protein levels. Compound AK-2 suggested good oral absorption via pharmacokinetic studies and displayed a good and stable ligand-protein interaction in in-silico molecular modeling analysis. Thus, the compound AK-2 can be regarded as a lead molecule and should be investigated further for the treatment of AD.
ESTHER : Verma_2024_Eur.J.Med.Chem_271_116450
PubMedSearch : Verma_2024_Eur.J.Med.Chem_271_116450
PubMedID: 38701714

Title : Insect immune resolution with EpOME\/DiHOME and its dysregulation by their analogs leading to pathogen hypersensitivity - Hossain_2024_Insect.Biochem.Mol.Biol__104104
Author(s) : Hossain Hrithik MT , Shahmohammadi N , Jin G , Lee DH , Singh N , Vik A , Hammock BD , Kim Y
Ref : Insect Biochemistry & Molecular Biology , :104104 , 2024
Abstract : Upon immune challenge, recognition signals trigger insect immunity to remove the pathogens through cellular and humoral responses. Various immune mediators propagate the immune signals to nearby tissues, in which polyunsaturated fatty acid (PUFA) derivatives play crucial roles. However, little was known on how the insects terminate the activated immune responses after pathogen neutralization. Interestingly, C20 PUFA was detected at the early infection stage and later C18 PUFAs were induced in a lepidopteran insect, Spodoptera exigua. This study showed the role of epoxyoctadecamonoenoic acids (EpOMEs) in the immune resolution at the late infection stage to quench the excessive and unnecessary immune responses. In contrast, dihydroxy-octadecamonoenoates (DiHOMEs) were the hydrolyzed and inactive forms of EpOMEs. The hydrolysis is catalyzed by soluble epoxide hydrolase (sEH). Inhibitors specific to sEH mimicked the immunosuppression induced by EpOMEs. Furthermore, the inhibitor treatments significantly enhanced the bacterial virulence of Bacillus thuringiensis against S. exigua. This study proposes a negative control of the immune responses using EpOME/DiHOME in insects.
ESTHER : Hossain_2024_Insect.Biochem.Mol.Biol__104104
PubMedSearch : Hossain_2024_Insect.Biochem.Mol.Biol__104104
PubMedID: 38494144

Title : Insect immune resolution with EpOME\/DiHOME and its dysregulation by their analogs leading to pathogen hypersensitivity - Hrithrik_2023_bioRxiv__
Author(s) : Hrithrik MTH , Lee DH , Singh N , Vik A , Hammock BD , Kim Y
Ref : Biorxiv , : , 2023
Abstract : Epoxyoctadecamonoenoic acids (EpOMEs) are epoxide derivatives of linoleic acid (9,12-octadecadienoic acid: LA). They are metabolized into dihydroxyoctadecamonoenoic acids (DiHOMEs) in mammals. Unlike in mammals where they act as adipokines or lipokines, EpOMEs act as immunosuppressants in insects. However, the functional link between EpOMEs and pro-immune mediators such as PGE (2) is not known. In addition, the physiological significance of DiHOMEs is not clear in insects. This study analyzed the physiological role of these C18 oxylipins using a lepidopteran insect pest, Spodoptera exigua . Immune challenge of S. exigua rapidly upregulated the expression of the phospholipase A (2) gene to trigger C20 oxylipin biosynthesis, followed by the upregulation of genes encoding EpOME synthase ( SE51385 ) and a soluble epoxide hydrolase ( Se-sEH ). The sequential gene expression resulted in the upregulations of the corresponding gene products such as PGE (2) , EpOMEs, and DiHOMEs. Interestingly, only PGE (2) injection without the immune challenge significantly upregulated the gene expression of SE51825 and Se-sEH . The elevated levels of EpOMEs acted as immunosuppressants by inhibiting cellular and humoral immune responses induced by the bacterial challenge, in which 12,13-EpOME was more potent than 9,10-EpOME. However, DiHOMEs did not inhibit the cellular immune responses but upregulated the expression of antimicrobial peptides selectively suppressed by EpOMEs. The negative regulation of insect immunity by EpOMEs and their inactive DiHOMEs were further validated by synthetic analogs of the linoleate epoxide and corresponding diol. Furthermore, inhibitors specific to Se-sEH used to prevent EpOME degradation significantly suppressed the immune responses. The data suggest a physiological role of C18 oxylipins in resolving insect immune response. Any immune dysregulation induced by EpOME analogs or sEH inhibitors significantly enhanced insect susceptibility to the entomopathogen, Bacillus thuringiensis . AUTHOR SUMMARY: Upon immune challenge, recognition signal triggers insect immunity to remove the pathogens by cellular and humoral responses. Various immune mediators propagate the immune signals to nearby tissues, in which polyunsaturated fatty acid (PUFA) derivatives play crucial roles. However, little was known on how the insects terminate the activated immune responses after pathogen neutralization. Interestingly, C20 PUFA was detected at the early infection stage and later C18 PUFAs were induced in a lepidopteran insect, Spodoptera exigua . This study showed the role of epoxyoctadecamonoenoic acids (EpOMEs) in the immune resolution at the late infection stage to quench the excessive and unnecessary immune responses. In contrast, dihydroxy-octadecamonoenoates (DiHOMEs) were the hydrolyzed and inactive forms of EpOMEs. The hydrolysis is catalyzed by soluble epoxide hydrolase (sEH). Inhibitors specific to sEH mimicked the immunosuppression induced by EpOMEs. Furthermore, the inhibitor treatments significantly enhanced the bacterial virulence of Bacillus thuringiensis against S. exigua . This study proposes a negative control of the immune responses using EpOME/DiHOME in insects.
ESTHER : Hrithrik_2023_bioRxiv__
PubMedSearch : Hrithrik_2023_bioRxiv__
PubMedID: 37461499

Title : Extraction, isolation, synthesis, and biological evaluation of novel piperic acid derivatives for the treatment of Alzheimer's disease - Kumar_2023_Mol.Divers__
Author(s) : Kumar J , Shankar G , Kumar S , Thomas J , Singh N , Srikrishna S , Satija J , Krishnamurthy S , Modi G , Mishra SK
Ref : Mol Divers , : , 2023
Abstract : In this paper, we developed a series of piperic acid (PA) analogs with the aim of overcoming the limitations associated with the natural products for the management of Alzheimer's disease (AD). A comprehensive SAR study was performed to enhance cholinesterase inhibition of PA. The acetylcholinesterase inhibition and its kinetic data suggested 6j as the lead molecule (AChE IC(50) = 2.13 +/- 0.015 microM, BChE = 28.19 +/- 0.20%), in comparison to PA (AChE = 7.14 +/- 0.98%) which was further selected for various biological studies in AD models. 6j, exhibited interaction with the peripheral anionic site of AChE, BBB permeability (Pe = 7.98), and antioxidant property (% radical scavenging activity = 35.41 +/- 1.09, 2.43 +/- 1.65, for 6j and PA at 20 M[Formula: see text], respectively). The result from the metal chelation study suggests that 6j did not effectively chelate iron. The molecular modeling studies suggested that 6j could effectively interact with Ser293, Phe295, Arg296, and Tyr34 of AChE. In the cell-based cytotoxicity studies, 6j exhibited cytocompatibility at the different tested concentrations. The acute toxicity data on mice suggested that compound 6j had no renal and hepatotoxicity at 500 mg/kg. Moreover, 6j could effectively reverse scopolamine-induced amnesia by improving spatial and cognitive memory in mice. The above results strongly suggest that compound 6j may act as a novel multi-targeted lead for AD therapy.
ESTHER : Kumar_2023_Mol.Divers__
PubMedSearch : Kumar_2023_Mol.Divers__
PubMedID: 37351693

Title : Design, Synthesis, and Biological Evaluation of Piperazine and N-Benzylpiperidine Hybrids of 5-Phenyl-1,3,4-oxadiazol-2-thiol as Potential Multitargeted Ligands for Alzheimer's Disease Therapy - Waiker_2023_ACS.Chem.Neurosci__
Author(s) : Waiker DK , Verma A , Akhilesh , Gajendra TA , Singh N , Roy A , Dilnashin H , Tiwari V , Trigun SK , Singh SP , Krishnamurthy S , Lama P , Davisson VJ , Shrivastava SK
Ref : ACS Chem Neurosci , : , 2023
Abstract : Our present work demonstrates the successful design and synthesis of a new class of compounds based upon a multitargeted directed ligand design approach to discover new agents for use in Alzheimer's disease (AD). All the compounds were tested for their in vitro inhibitory potential against human acetylcholinesterase (hAChE), human butylcholinesterase (hBChE), beta-secretase-1 (hBACE-1), and amyloid beta (Abeta) aggregation. Compounds 5d and 5f have shown hAChE and hBACE-1 inhibition comparable to donepezil, while hBChE inhibition was comparable to rivastigmine. Compounds 5d and 5f also demonstrated a significant reduction in the formation of Abeta aggregates through the thioflavin T assay and confocal, atomic force, and scanning electron microscopy studies and significantly displaced the total propidium iodide, that is, 54 and 51% at 50 microM concentrations, respectively. Compounds 5d and 5f were devoid of neurotoxic liabilities against RA/BDNF (RA = retinoic acid; BDNF = brain-derived neurotrophic factor)-differentiated SH-SY5Y neuroblastoma cell lines at 10-80 microM concentrations. In both the scopolamine- and Abeta-induced mouse models for AD, compounds 5d and 5f demonstrated significant restoration of learning and memory behaviors. A series of ex vivo studies of hippocampal and cortex brain homogenates showed that 5d and 5f elicit decreases in AChE, malondialdehyde, and nitric oxide levels, an increase in glutathione level, and reduced levels of pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) mRNA. The histopathological examination of mice revealed normal neuronal appearance in the hippocampal and cortex regions of the brain. Western blot analysis of the same tissue indicated a reduction in Abeta, amyloid precursor protein (APP)/Abeta, BACE-1, and tau protein levels, which were non-significant compared to the sham group. The immunohistochemical analysis also showed significantly lower expression of BACE-1 and Abeta levels, which was comparable to donepezil-treated group. Compounds 5d and 5f represent new lead candidates for developing AD therapeutics.
ESTHER : Waiker_2023_ACS.Chem.Neurosci__
PubMedSearch : Waiker_2023_ACS.Chem.Neurosci__
PubMedID: 37216500

Title : Soluble Epoxide Hydrolase Contributes to Cell Senescence and ER Stress in Aging Mice Colon - Wang_2023_Int.J.Mol.Sci_24_4570
Author(s) : Wang W , Wagner KM , Wang Y , Singh N , Yang J , He Q , Morisseau C , Hammock BD
Ref : Int J Mol Sci , 24 :4570 , 2023
Abstract : Aging, which is characterized by enhanced cell senescence and functional decline of tissues, is a major risk factor for many chronic diseases. Accumulating evidence shows that age-related dysfunction in the colon leads to disorders in multiple organs and systemic inflammation. However, the detailed pathological mechanisms and endogenous regulators underlying colon aging are still largely unknown. Here, we report that the expression and activity of the soluble epoxide hydrolase (sEH) enzyme are increased in the colon of aged mice. Importantly, genetic knockout of sEH attenuated the age-related upregulation of senescent markers p21, p16, Tp53, and beta-galactosidase in the colon. Moreover, sEH deficiency alleviated aging-associated endoplasmic reticulum (ER) stress in the colon by reducing both the upstream regulators Perk and Ire1 as well as the downstream pro-apoptotic effectors Chop and Gadd34. Furthermore, treatment with sEH-derived linoleic acid metabolites, dihydroxy-octadecenoic acids (DiHOMEs), decreased cell viability and increased ER stress in human colon CCD-18Co cells in vitro. Together, these results support that the sEH is a key regulator of the aging colon, which highlights its potential application as a therapeutic target for reducing or treating age-related diseases in the colon.
ESTHER : Wang_2023_Int.J.Mol.Sci_24_4570
PubMedSearch : Wang_2023_Int.J.Mol.Sci_24_4570
PubMedID: 36901999

Title : Design and development of benzyl piperazine linked 5-phenyl-1,2,4-triazole-3-thione conjugates as potential agents to combat Alzheimer's disease - Kiran_2023_Bioorg.Chem_139_106749
Author(s) : Kiran PVR , Waiker DK , Verma A , Saraf P , Bhardwaj B , Kumar H , Singh A , Kumar P , Singh N , Srikrishna S , Trigun SK , Shrivastava SK
Ref : Bioorg Chem , 139 :106749 , 2023
Abstract : Our present work demonstrates the molecular hybridization-assisted design, synthesis, and biological evaluation of 22 benzylpiperazine-linked 1,2,4-triazole compounds (PD1-22) as AD modifying agents. All the compounds were tested for their in vitro hChEs, hBACE-1, and Abeta-aggregation inhibition properties. Among them, compound PD-08 and PD-22 demonstrated good hChE and hBACE-1 inhibition as compared to standards donepezil and rivastigmine. Both compounds displaced PI from PAS at 50 microM concentration which was comparable to donepezil and also demonstrated anti-Abeta aggregation properties in self- and AChE-induced thioflavin T assay. Both compounds have shown excellent BBB permeation via PAMPA-BBB assay and were found to be non-neurotoxic at 80 microM concentration against differentiated SH-SY5Y cell lines. Compound PD-22 demonstrated an increase in rescued eye phenotype in Abeta-phenotypic drosophila AD model and amelioration of behavioral deficits in the Abeta-induced rat model of AD. The in-silico docking studies of compound PD-22 revealed a good binding profile towards CAS and PAS residues of AChE and the catalytic dyad of the BACE-1. The 100 ns molecular dynamics simulation studies of compound PD-22 complexed with AChE and BACE-1 enzymes suggested stable ligand-protein complex throughout the simulation run. Based on our findings compound PD-22 could further be utilized as a lead to design a promising candidate for AD therapy.
ESTHER : Kiran_2023_Bioorg.Chem_139_106749
PubMedSearch : Kiran_2023_Bioorg.Chem_139_106749
PubMedID: 37517157

Title : Aflatoxin B(1) exposure disrupts the intestinal immune function via a soluble epoxide hydrolase-mediated manner - Wang_2022_Ecotoxicol.Environ.Saf_249_114417
Author(s) : Wang W , Wang Y , Yang J , Wagner KM , Hwang SH , Cheng J , Singh N , Edwards P , Morisseau C , Zhang G , Panigrahy D , Hammock BD
Ref : Ecotoxicology & Environmental Safety , 249 :114417 , 2022
Abstract : Aflatoxin B(1) (AFB(1)) contamination in food and feed leads to severe global health problems. Acting as the frontier immunological barrier, the intestinal mucosa is constantly challenged by exposure to foodborne toxins such as AFB(1) via contaminated diets, but the detailed toxic mechanism and endogenous regulators of AFB(1) toxicity are still unclear. Here, we showed that AFB(1) disrupted intestinal immune function by suppressing macrophages, especially M2 macrophages, and antimicrobial peptide-secreting Paneth cells. Using an oxylipinomics approach, we identified that AFB(1) immunotoxicity is associated with decreased epoxy fatty acids, notably epoxyeicosatrienoic acids, and increased soluble epoxide hydrolase (sEH) levels in the intestine. Furthermore, sEH deficiency or inhibition rescued the AFB(1)-compromised intestinal immunity by restoring M2 macrophages as well as Paneth cells and their-derived lysozyme and alpha-defensin-3 in mice. Altogether, our study demonstrates that AFB(1) exposure impairs intestinal immunity, at least in part, in a sEH-mediated way. Moreover, the present study supports the potential application of pharmacological intervention by inhibiting the sEH enzyme in alleviating intestinal immunotoxicity and associated complications caused by AFB(1) global contamination.
ESTHER : Wang_2022_Ecotoxicol.Environ.Saf_249_114417
PubMedSearch : Wang_2022_Ecotoxicol.Environ.Saf_249_114417
PubMedID: 36525946

Title : sEH-derived metabolites of linoleic acid drive pathologic inflammation while impairing key innate immune cell function in burn injury - Bergmann_2022_Proc.Natl.Acad.Sci.U.S.A_119_e2120691119
Author(s) : Bergmann CB , McReynolds CB , Wan D , Singh N , Goetzman H , Caldwell CC , Supp DM , Hammock BD
Ref : Proc Natl Acad Sci U S A , 119 :e2120691119 , 2022
Abstract : Significance: Oxylipins alter immune cell function and potentially drive pathophysiology in burn and sepsis patients. Past and recent data reveal a correlation between increased systemic EpOME levels and reduced survival in human burn trauma and sepsis. This work extends these studies and provides evidence that the downstream sEH-derived metabolites, DiHOMEs, are driving worsening outcomes by altering the immune response. Inhibiting DiHOME metabolite formation with the sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), restored immune function by increasing immune cell survival and function. These data support the hypothesis that sEH-derived linoleic acid diols are responsible for increased mortality in burn and sepsis patients and also provide a rationale for testing the therapeutic blockage of DiHOME generation in burn and sepsis patients to improve their outcomes.
ESTHER : Bergmann_2022_Proc.Natl.Acad.Sci.U.S.A_119_e2120691119
PubMedSearch : Bergmann_2022_Proc.Natl.Acad.Sci.U.S.A_119_e2120691119
PubMedID: 35312372

Title : Thromboxane A2 synthase inhibition ameliorates endothelial dysfunction, memory deficits, oxidative stress and neuroinflammation in rat model of streptozotocin diabetes induced dementia - Bhatia_2021_Physiol.Behav_241_113592
Author(s) : Bhatia P , Singh N
Ref : Physiol Behav , 241 :113592 , 2021
Abstract : RATIONALE: Vascular dementia (VaD) is the second leading cause of dementia worldwide. It is very important to find the possible pharmacological agents which may be useful in management and therapy of VaD. OBJECTIVES: The present study investigates the effect of ozagrel, a selective thromboxane A2 (TXA2) synthase inhibitor, in a rat model of VaD. METHODS: Single intraperitoneal injection of streptozotocin [STZ, (50 mg/kg)] was administered to Wistar rats to induced diabetes-associated vascular endothelial dysfunction and memory impairment. Morris water maze (MWM) test was employed to assess learning and memory. Endothelial dysfunction was assessed in the isolated aorta by observing endothelial-dependent vasorelaxation and levels of serum nitrite. Various biochemical and histopathological estimations were also performed. RESULTS: STZ treatment produced endothelial dysfunction, impairment of learning and memory, reduction in body weight and serum nitrite/nitrate, and increase in serum glucose, brain oxidative stress (increased brain thiobarbituric acid reactive species and decreased reduced glutathione levels), brain acetylcholinesterase activity and brain myeloperoxidase activity. Further a significant rise in brain tumor necrosis factor-alpha & interleukin-6 levels and brain neutrophil infiltration were also observed. Treatment of ozagrel (10 & 20 mg/kg, p. o.)/donepezil (0. 5 mg/kg, i.p., serving as standard) ameliorated STZ induced endothelial dysfunction; memory deficits; biochemical and histopathological changes. CONCLUSIONS: It may be concluded that ozagrel markedly improved endothelial dysfunction; learning and memory; biochemical and histopathological alteration associated with STZ induced dementia and that TXA2 can be considered as an important therapeutic target for the management of VaD.
ESTHER : Bhatia_2021_Physiol.Behav_241_113592
PubMedSearch : Bhatia_2021_Physiol.Behav_241_113592
PubMedID: 34534530

Title : Adrenic Acid-Derived Epoxy Fatty Acids Are Naturally Occurring Lipids and Their Methyl Ester Prodrug Reduces Endoplasmic Reticulum Stress and Inflammatory Pain - Singh_2021_ACS.Omega_6_7165
Author(s) : Singh N , Barnych B , Wagner KM , Wan D , Morisseau C , Hammock BD
Ref : ACS Omega , 6 :7165 , 2021
Abstract : Adrenic acid (AdA, 22:4) is an omega-6 polyunsaturated fatty acid (PUFA), derived from arachidonic acid. Like other PUFAs, it is metabolized by cytochrome P450s to a group of epoxy fatty acids (EpFAs), epoxydocosatrienoic acids (EDTs). EpFAs are lipid mediators with various beneficial bioactivities, including exertion of analgesia and reduction of endoplasmic reticulum (ER) stress, that are degraded to dihydroxy fatty acids by the soluble epoxide hydrolase (sEH). However, the biological characteristics and activities of EDTs are relatively unexplored, and, alongside dihydroxydocosatrienoic acids (DHDTs), they had not been detected in vivo. Herein, EDT and DHDT regioisomers were synthesized, purified, and used as standards for analysis with a selective and quantitative high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. Biological verification in AdA-rich tissues suggests that basal metabolite levels are highest in the liver, with 16,17-EDT concentrations consistently being the greatest across the analyzed tissues. Enzyme hydrolysis assessment revealed that EDTs are sEH substrates, with greatest relative rate preference for the 13,14-EDT regioisomer. Pretreatment with an EDT methyl ester regioisomer mixture significantly reduced the onset of tunicamycin-stimulated ER stress in human embryonic kidney cells. Finally, administration of the regioisomeric mixture effectively alleviated carrageenan-induced inflammatory pain in rats. This study indicates that EDTs and DHDTs are naturally occurring lipids, and EDTs could be another therapeutically relevant group of EpFAs.
ESTHER : Singh_2021_ACS.Omega_6_7165
PubMedSearch : Singh_2021_ACS.Omega_6_7165
PubMedID: 33748630

Title : Ameliorative role of rolipram, PDE-4 inhibitor, against sodium arsenite-induced vascular dementia in rats - Virk_2021_Environ.Sci.Pollut.Res.Int__
Author(s) : Virk D , Kumar A , Jaggi AS , Singh N
Ref : Environ Sci Pollut Res Int , : , 2021
Abstract : Arsenic exposure to the population leads to serious health problems like neurotoxicity, nephrotoxicity, and cardiovascular abnormality. In the present study, the work has been commenced to discover the prospect of rolipram a phosphodiestrase-4 (PDE-4) inhibitor against sodium arsenite (SA)-induced vascular endothelial dysfunction (EnDF) leading to dementia in rats. Wistar rats were treated with SA (5 mg/kg body weight/day orally) for 44 days for induction of vascular EnDF and dementia. Learning and memory were evaluated using Morris water maze (MWM) test. Vascular EnDF was evaluated using aortic ring preparation. Various biochemical parameters were also evaluated like brain oxidative stress (viz. reduced glutathione and thiobarbituric acid reactive substances level), serum nitrite/nitrate activity, acetylcholinesterase activity, and inflammatory markers (viz. neutrophil infiltration in brain and myeloperoxidase). SA-treated rats showed poor performance in water maze trials indicating attenuated memory and ability to learn with significant rise (p < 0.05) in brain acetylcholinesterase activity, brain oxidative stress, neutrophil count, and significant decrease (p < 0.05) in serum nitrite/nitrate levels and vascular endothelial functions. Rolipram (PDE-4 inhibitor) treatment (0.03 mg/kg and 0.06 mg/kg body weight, intraperitoneally daily for 14 days) significantly improved memory and learning abilities, and restored various biochemical parameters and EnDF. It is concluded that PDE-4 modulator may be considered the prospective target for the treatment of SA-induced vascular EnDF and related dementia.
ESTHER : Virk_2021_Environ.Sci.Pollut.Res.Int__
PubMedSearch : Virk_2021_Environ.Sci.Pollut.Res.Int__
PubMedID: 34226994

Title : Paraoxonase Mimic by a Nanoreactor Aggregate Containing Benzimidazolium Calix and l-Histidine: Demonstration of the Acetylcholine Esterase Activity - Singh_2021_Chemistry_27_5737
Author(s) : Singh A , Saini S , Mayank , Kaur N , Singh N , Jang DO
Ref : Chemistry , 27 :5737 , 2021
Abstract : An anion-mediated preorganization approach was used to design and synthesize the benzimidazolium-based calix compound R1 2ClO(4) (-) . X-ray crystallography analysis revealed that the hydrogen-bonding interactions between the benzimidazolium cations and N,N-dimethylformamide (DMF) helped R1 2ClO(4) (-) encapsulate DMF molecule(s). A nanoreactor, with R1 2ClO(4) (-) and l-histidine (l-His) as the components, was fabricated by using a neutralization method. The nanoreactor could detoxify paraoxon in 30min. l-His played a vital role in this process. Paraoxonase is a well-known enzyme used for pesticide degradation. The Ellman's reagent was used to determine the percentage inhibition of the acetylcholinesterase (AChE) activity in the presence of the nanoreactor. The results indicated that the nanoreactor inhibited AChE inhibition.
ESTHER : Singh_2021_Chemistry_27_5737
PubMedSearch : Singh_2021_Chemistry_27_5737
PubMedID: 33350530

Title : Genetic polymorphisms in the mEH gene in relation to tobacco smoking: role in lung cancer susceptibility and survival in north Indian patients with lung cancer undergoing platinum-based chemotherapy - Walia_2021_Future.Oncol__
Author(s) : Walia HK , Singh N , Sharma S
Ref : Future Oncol , : , 2021
Abstract : Aim: Epoxide hydrolase is involved in oxidative defenses and is responsible for the activation of carcinogens. The relationship between EPHX1 polymorphisms (Tyr(113)His and His(139)Arg) and overall survival (OS) and lung cancer (LC) risk was investigated. Methods: The study comprised 550 cases and 550 controls. Genotyping and statistical analysis were applied. Results: The variant genotypes of EPHX1 polymorphisms exhibited no association with LC risk. The Tyr(113)His polymorphism exhibited twofold increased odds of lymph node invasion (p = 0.04). The Tyr/His genotype is a risk factor for smokers. Subjects carrying the combined genotype for His(139)Arg showed better median survival time (MST) and the heterozygous genotype revealed better MST in the case of small-cell lung cancer (SCLC; 11.30 vs 6.73 months; log-rank test: p = 0.02). The heterozygous genotype (His139Arg) had longer MST in patients receiving cisplatin/carboplatin and irinotecan (11.30 vs 7.23; log-rank test: p = 0.007) Conclusion: The Tyr(113)His polymorphism is associated with LC risk in smokers and is a potential prognostic factor for OS in patients with SCLC after irinotecan.
ESTHER : Walia_2021_Future.Oncol__
PubMedSearch : Walia_2021_Future.Oncol__
PubMedID: 34672683

Title : New Alkoxy- Analogues of Epoxyeicosatrienoic Acids Attenuate Cisplatin Nephrotoxicity In Vitro via Reduction of Mitochondrial Dysfunction, Oxidative Stress, Mitogen-Activated Protein Kinase Signaling, and Caspase Activation - Singh_2021_Chem.Res.Toxicol__
Author(s) : Singh N , Vik A , Lybrand DB , Morisseau C , Hammock BD
Ref : Chemical Research in Toxicology , : , 2021
Abstract : The usage of cisplatin, a highly potent chemotherapeutic, is limited by its severe nephrotoxicity. Arachidonic acid (ARA)-derived epoxyeicosatrienoic acids (EETs) and soluble epoxide hydrolase (sEH) inhibitors were shown to ameliorate this dose-limiting side effect, but both approaches have some pharmacological limitations. Analogues of EETs are an alternative avenue with unique benefits, but the current series of analogues face concerns regarding their structure and mimetic functionality. Hence, in this study, regioisomeric mixtures of four new ARA alkyl ethers were synthesized, characterized, and assessed as EET analogues against the concentration- and time-dependent toxicities of cisplatin in porcine proximal tubular epithelial cells. All four ether groups displayed bioisostere activity, ranging from marginal for methoxy- (1), good for n-propoxy- (4), and excellent for ethoxy- (2) and i-propoxy- (3). Compounds 2 and 3 displayed cytoprotective effects comparable to that of an EET regioisomeric mixture (5) against high, acute cisplatin exposures but were more potent against low to moderate, chronic exposures. Compounds 2 and 3 (and 5) acted through stabilization of the mitochondrial transmembrane potential and attenuation of reactive oxygen species, leading to reduced phosphorylation of mitogen-activated protein kinases p38 and JNK and decreased activation of caspase-9 and caspase-3. This study demonstrates that alkoxy- groups are potent and more metabolically stable bioisostere alternatives to the epoxide within EETs that enable sEH-independent activity. It also illustrates the potential of ether-based mimics of EETs and other epoxy fatty acids as promising nephroprotective agents to tackle the clinically relevant side effect of cisplatin without compromising its antineoplastic function.
ESTHER : Singh_2021_Chem.Res.Toxicol__
PubMedSearch : Singh_2021_Chem.Res.Toxicol__
PubMedID: 34817988

Title : Pharmacological investigations on efficacy of Phlorizin a sodium-glucose co-transporter (SGLT) inhibitor in mouse model of intracerebroventricular streptozotocin induced dementia of AD type - Rani_2021_J.Basic.Clin.Physiol.Pharmacol__
Author(s) : Rani R , Kumar A , Jaggi AS , Singh N
Ref : J Basic Clin Physiol Pharmacol , : , 2021
Abstract : OBJECTIVES: The study has been commenced to discover the potential of Phlorizin (dual SGLT inhibitor) in streptozotocin induced dementia of Alzheimer's disease (AD) type. MATERIAL AND METHODS: Injection of Streptozotocin (STZ) was given via i.c.v. route (3 mg/kg) to induce dementia of Alzheimer's type. In these animals learning and memory was evaluated using Morris water maze (MWM) test. Glutathione (GSH) and thiobarbituric acid reactive species (TBARS) level was quantified to evaluate the oxidative stress; cholinergic activity of brain was estimated in term of acetylcholinesterase (AChE) activity; and the levels of myeloperoxidase (MPO) were measured as inflammation marker. RESULTS: The mice model had decreased performance in MWM, representing impairment of cognitive functions. Biochemical evaluation showed rise in TBARS level, MPO and AChE activity, and fall in GSH level. The histopathological study revealed severe infiltration of neutrophils. In the study, Phlorizin/Donepezil (serving as positive control) treatment mitigate streptozotocin induced cognitive decline, histopathological changes and biochemical alterations. CONCLUSIONS: The results suggest that Phlorizin decreased cognitive function via its anticholinesterase, antioxidative, antiinflammatory effects and probably through SGLT inhibitory action. It can be conferred that SGLTs can be an encouraging target for the treatment of dementia of AD.
ESTHER : Rani_2021_J.Basic.Clin.Physiol.Pharmacol__
PubMedSearch : Rani_2021_J.Basic.Clin.Physiol.Pharmacol__
PubMedID: 33548170

Title : Tadalafil ameliorates memory deficits, oxidative stress, endothelial dysfunction and neuropathological changes in rat model of hyperhomocysteinemia induced vascular dementia - Bhatia_2020_Int.J.Neurosci__1
Author(s) : Bhatia P , Singh N
Ref : International Journal of Neuroscience , :1 , 2020
Abstract : The present study investigates the potential of tadalafil, a phosphodiesterase-5 inhibitor, in a rat model of hyperhomocysteinemia induced vascular dementia. Hyperhomocysteinemia induced vascular dementia in Wistar rats was produced by administering L-Methionine (1.7g/kg/day; p.o. x 8 weeks). Learning and memory was assessed by employing Morris water maze (MWM) test. Endothelial dysfunction was assessed through acetylcholine-induced endothelial-dependent vasorelaxation and serum nitrite levels. Various other biochemical and histopathological estimations were also performed. L-Methionine produced significant impairment in acetylcholine-induced endothelium-dependent vasorelaxation and a decrease in serum nitrite levels indicating endothelial dysfunction. Further, these animals performed poorly on Morris water maze, depicting impairment of learning and memory. There was a significant rise in brain oxidative stress level (indicated by an increase in brain thiobarbituric acid reactive species and a decrease in reduced glutathione levels). Increase in brain acetylcholinesterase activity; brain myeloperoxidase activity and brain neutrophil infiltration (a marker of inflammation) were also observed. Tadalafil (5 & 10 mg/kg, p.o.)/donepezil (0.5 mg/kg, i.p., serving as standard) treatment ameliorated L-Methionine induced endothelial dysfunction; memory deficits; biochemical and histopathological changes in a significant manner. It may be concluded that tadalafil has shown efficacy in the rat model of L-Methionine induced vascular dementia and that phosphodiesterase-5 can be considered as an important therapeutic target for the treatment of vascular dementia.
ESTHER : Bhatia_2020_Int.J.Neurosci__1
PubMedSearch : Bhatia_2020_Int.J.Neurosci__1
PubMedID: 32859137

Title : Ozagrel a thromboxane A2 synthase inhibitor extenuates endothelial dysfunction, oxidative stress and neuroinflammation in rat model of bilateral common carotid artery occlusion induced vascular dementia - Bhatia_2020_Vascul.Pharmacol__106827
Author(s) : Bhatia P , Kaur G , Singh N
Ref : Vascul Pharmacol , :106827 , 2020
Abstract : The present study investigates the potential of ozagrel, a thromboxane A2 (TXA2) synthase inhibitor, in bilateral common carotid artery occlusion (BCCAo) induced vascular dementia (VaD). Wistar rats were subjected to BCCAo procedure under anesthesia to induce VaD. Morris water maze (MWM) test was employed on 7th day post-surgery to determine learning and memory. Endothelial dysfunction was assessed in isolated aorta by observing endothelial dependent vasorelaxation and levels of serum nitrite. A battery of biochemical and histopathological estimations was performed. Expression analysis of inflammatory cytokines TNF-alpha and IL-6 was carried out by RT-PCR. BCCAo produced significant impairment in endothelium dependent vasorelaxation and decrease in serum nitrite levels indicating endothelial dysfunction along with poor performance on MWM represents impairment of learning and memory. There was a significant rise in brain oxidative stress level (indicated by increase in brain thiobarbituric acid reactive species and decrease in reduced glutathione levels); increase in brain acetylcholinesterase activity; brain myeloperoxidase activity; brain TNF-alpha & IL-6 levels, brain TNF-alpha & IL-6 mRNA expression and brain neutrophil infiltration (as marker of inflammation) were also observed. Treatment of ozagrel (10 & 20 mg/kg, p. o.)/donepezil (0. 5 mg/kg, i.p., serving as standard) ameliorated BCCAo induced endothelial dysfunction; memory deficits; biochemical and histopathological changes in a significant manner. It may be concluded that ozagrel markedly improved endothelial dysfunction; learning and memory; biochemical and histopathological alteration associated with BCCAo induced VaD and that TXA2 can be considered as an important therapeutic target for the treatment of VaD.
ESTHER : Bhatia_2020_Vascul.Pharmacol__106827
PubMedSearch : Bhatia_2020_Vascul.Pharmacol__106827
PubMedID: 33346090

Title : Interaction of Synthesized Nitrogen enriched Graphene Quantum Dots with Novel Anti-Alzheimer's Drugs: Spectroscopic Insights - Sharma_2020_J.Biomol.Struct.Dyn_38_1822
Author(s) : Sharma S , Singh N , Nepovimova E , Korabecny J , Kuca K , Satnami ML , Ghosh KK
Ref : J Biomol Struct Dyn , 38 :1822 , 2020
Abstract : Alzheimer's disease (AD) is considered as one of widespread dementia with no approved diagnosis, cure or prevention. Currently, only symptomatic relief can be provided upon administration of anti-AD drugs generally belonging to a category of anticholinesterases and antagonists of N-methyl-D-aspartate (NMDA) receptors. In present investigation, a sensing platform has been designed for studying recently developed anti-AD drugs viz., PC-25 (N-(2-{4-[(4-bromophenyl)methyl]piperazin-1-yl}ethyl)-7-methoxy-1,2,3,4-tetrahydr oacridin-9-amine trihydrochloride), PC-37 (7-methoxy-N-(2-{4-[(3-methylphenyl)methyl]piperazin-1-yl}ethyl)-1,2,3,4-tetrahyd roacridin-9-amine trihydrochloride) and PC-48 (N-(2-{4-[(3-bromophenyl) methyl]piperazin-1-yl}ethyl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine trihydrochloride) and two known standard tacrine (THA) and donepezil drugs for their estimation of in vitro potency towards AD using spectroscopic method. Anti-AD drugs have been accounted for individually with highly fluorescent nitrogen doped graphene quantum dots (NGQDs). The designed anti-AD drugs exerted the efficacy related to cholinergic hypothesis of AD. While the enzyme action is sensed by interacted species of NGQDs and acetylcholine, the fluorescence of NGQDs is quenched by the hydrolyzing action of acetylcholinesterase (AChE) enzyme but the lost fluorescence is recovered back upon addition of anti-AD drugs. These alterations in fluorescence of NGQDs are expected to have biological relevance akin to sensing. Moreover, these results advocate that out of all the drugs tested PC-37 displayed maximum inhibition efficiency. Our investigations suggest that synthesized drugs have the AD treating potential and can be entrusted in the near future for AD treatment. The validation parameters such as LOD, LOQ and recovery (%) were calculated in the range of 2.87 mM, 9.58 mM and 85-96%, respectively.
ESTHER : Sharma_2020_J.Biomol.Struct.Dyn_38_1822
PubMedSearch : Sharma_2020_J.Biomol.Struct.Dyn_38_1822
PubMedID: 31096863

Title : Constitutively active HCN channels constrain detrusor excitability and modulate evoked contractions of human bladder - Kashyap_2020_Am.J.Clin.Exp.Urol_8_163
Author(s) : Kashyap M , Singh N , Yoshimura N , Chermansky C , Tyagi P
Ref : Am J Clin Exp Urol , 8 :163 , 2020
Abstract : OBJECTIVE: Expression of Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels is reported in bladder, but the functional role remains unsettled. Here, we immunolocalized the HCN1 and HCN4 subtype in human bladder and investigated their functional significance. METHODS: Bladder procured from ten organ donors was dissected into mucosa (containing urothelium and submucosa) and detrusor for double immunofluorescence of HCN1 and 4 subtypes with gap junction and neural proteins together with isometric tension recordings. Mucosa intact and denuded detrusor strips were stretched to a basal tension of 10 mN for eliciting either tetrodotoxin (TTX) resistant spontaneous, carbachol evoked contractions and TTX sensitive electrical field stimulated (EFS), pre and post-addition of HCN blocker, ZD7288 or the activator, Lamotrigine or the cholinesterase inhibitor, Neostigmine. RESULTS: Double immunofluorescence revealed immunolocalization of HCN1 and HCN4 subtype with calcitonin gene related peptide (CGRP), choline acetyl transferase and gap junction proteins in mucosa and detrusor. Removal of mucosa significantly raised the resting tension and the force of spontaneous contractions upon cumulative addition of ZD7288 in micromolar range relative to Lamotrigine treated strips (P<0.05). ZD7288 [10 nM] did not affect the contractile response evoked by EFS or carbachol, but the addition of ZD7288 [10 nM] in presence of Neostigmine [1 microM] significantly enhanced the atropine and TTX sensitive EFS evoked contractions of mucosa denuded strips. CONCLUSIONS: Overall, HCN channels immunolocalized in mucosa, smooth muscle, gap junctions and nerve fibers exert a tonic constraint on detrusor excitability, enable spatio-temporal integration of evoked contractions and constrain the release of neurotransmitters, respectively. In contrast to the pacemaker role in other organs, findings argue for a non-pacemaking role of HCN channels in human bladder.
ESTHER : Kashyap_2020_Am.J.Clin.Exp.Urol_8_163
PubMedSearch : Kashyap_2020_Am.J.Clin.Exp.Urol_8_163
PubMedID: 33235894

Title : Kinetic characterization of rat brain acetylcholinesterase modulated by lead and cartap: the ameliorative effect of Citrus limon fruit juice - Singh_2020_J.Basic.Clin.Physiol.Pharmacol__
Author(s) : Singh N , Tiwari P , Sharma B
Ref : J Basic Clin Physiol Pharmacol , : , 2020
Abstract : Objectives Human exposure to heavy metals and pesticides is a worldwide major health problem. These environmental pollutants have been considered as the most neurotoxic agents and responsible to causing neurological toxicity. Plant-based therapeutic supplement may be used in the event of toxicity. Citrus limon contains several useful bioactive ingredients including flavonoids, dietary fiber, carotenoids, vitamins, pectin, minerals, and essential oils, which are responsible for its therapeutic potential. In the present investigation, we have studied the toxicity of heavy metals such as lead (Pb) and a carbamate pesticide such as cartap (Cp) on rat brain acetylcholinesterase (AChE). Methods The chemical characterization of C. limon involved determination of total antioxidants and 2,2-diphenyl-1-picryl-hydrazyl-hydrate free radical scavenging activity using known methods. The AChE activity and its kinetic characterization were performed by assaying the enzyme activity at varying substrate concentrations, pH, temperature, and time of reaction. Its different kinetic parameters such as K i , V max, K m , K cat, and K cat/K m were determined by using standard procedures. The amelioration potential of the extract was evaluated on the neurotransmission system of rat brain AChE treated with Pb, Cp, and their combination (Pb-Cp), considering their 50% inhibitory concentration (IC50) values. Results The optimal activity of rat brain AChE was recorded at 25 microg of protein, pH of 7.4, substrate concentration [S] of 0.5 mM, and temperature of 37.4-40 degreesC. The enzyme was stable for 10 min when incubated at 37.4 degreesC in vitro. The enzyme displayed 70% of its activity remaining even after 160 min of incubation in this condition. It may be stable up to 1 month when stored at -20 degreesC. The IC50 values for Pb, Cp, and Pb-Cp were found to be 75, 2.9, and 5 mM, respectively. Pb, Cp, and Pb-Cp inhibited the activity of rat brain AChE in the noncompetitive, mixed, and uncompetitive manners, respectively, with their respective K i values to be 675, 2.37, and 22.72 mM. Conclusions The results indicated that the Pb and Cp were able to cause significant alterations in the level and properties of AChE. However, the introduction of lemon juice on Pb- and Cp-treated AChE indicated protection of its activity from their adverse effects. The results may be useful in prospective therapeutic applications of lemon juice or as a food supplement to protect mammalian systems from adverse effects of these toxicants.
ESTHER : Singh_2020_J.Basic.Clin.Physiol.Pharmacol__
PubMedSearch : Singh_2020_J.Basic.Clin.Physiol.Pharmacol__
PubMedID: 32924379

Title : A comprehensive review on ethnomedicine, phytochemistry, pharmacology, and toxicity of Tephrosia purpurea (L.) Pers - Rao_2020_Phytother.Res__
Author(s) : Rao AS , Yadav SS , Singh P , Nandal A , Singh N , Ganaie SA , Yadav N , Kumar R , Bhandoria MS , Bansal P
Ref : Phytother Res , : , 2020
Abstract : Tephrosia purpurea (L.) Pers. is a well-known plant in Ayurveda and named "Sarwa wranvishapaka" for its property to heal wounds. Traditionally, it is practiced for impotency, asthma, dyspepsia, hemorrhoids, syphilis gonorrhea, rheumatism, enlargement of kidney and spleen. It is an important component of herbal preparations like Tephroli and Yakrifti used to cure liver disorders. Various phytocompounds including pongamol, purpurin, purpurenone, tephrosin, bulnesol, tephrostachin, beta-sitosterol, and so on have been reported. Modern pharmacological studies have shown that the plant have wound healing, antileishmanial, anticarcinogenic, antimicrobial, antioxidant, hepatoprotective, antifertility, antispermatogenic, anti-diarrheal, diuretic, and insecticidal properties. Acetylcholinesterase inhibitory action reported from this plant aids its utilization for the development of drugs for Alzheimer's and dementia neurological disorders. Among the known active compounds of T. purpurea, tephrostachin is responsible for antiplasmodial activity, tephrosin, pongaglabol, and semiglabrin exerts antiulcer activity while quercetin, rutin, beta-sitosterol, and lupeol are mainly responsible for its anti-inflammatory and anti-cancer properties. From different toxicological studies, concentrations up to 2,000 mg/kg were considered safe. The present review comprehensively summarizes the ethnomedicine, phytochemistry, pharmacology, and toxicology of T. purpurea. Further research on elucidation of the structure-function relationship among active compounds, understanding of multi-target network pharmacology and clinical applications will intensify its therapeutic potential.
ESTHER : Rao_2020_Phytother.Res__
PubMedSearch : Rao_2020_Phytother.Res__
PubMedID: 32147928

Title : N-Benzyl-linoleamide, a Constituent of Lepidium meyenii (Maca), Is an Orally Bioavailable Soluble Epoxide Hydrolase Inhibitor That Alleviates Inflammatory Pain - Singh_2020_J.Nat.Prod_83_3689
Author(s) : Singh N , Barnych B , Morisseau C , Wagner KM , Wan D , Takeshita A , Pham H , Xu T , Dandekar A , Liu JY , Hammock BD
Ref : Journal of Natural Products , 83 :3689 , 2020
Abstract : Lepidium meyenii (maca), a plant indigenous to the Peruvian Andes, recently has been utilized globally for claimed health or recreational benefits. The search for natural products that inhibit soluble epoxide hydrolase (sEH), with therapeutically relevant potencies and concentrations, led to the present study on bioactive amide secondary metabolites found in L. meyenii, the macamides. Based on known and suspected macamides, 19 possible macamides were synthesized and characterized. The majority of these amides displayed excellent inhibitory potency (IC(50) = 20-300 nM) toward the recombinant mouse, rat, and human sEH. Quantitative analysis of commercial maca products revealed that certain products contain known macamides (1-5, 8-12) at therapeutically relevant total concentrations (<=3.29 mg/g of root), while the inhibitory potency of L. meyenii extracts directly correlates with the sum of concentration/IC(50) ratios of macamides present. Considering both its in vitro efficacy and high abundance in commercial products, N-benzyl-linoleamide (4) was identified as a particularly relevant macamide that can be utilized for in vivo studies. Following oral administration in the rat, compound 4 not only displayed acceptable pharmacokinetic characteristics but effectively reduced lipopolysaccharide-induced inflammatory pain. Inhibition of sEH by macamides provides a plausible biological mechanism of action to account for several beneficial effects previously observed with L. meyenii treatments.
ESTHER : Singh_2020_J.Nat.Prod_83_3689
PubMedSearch : Singh_2020_J.Nat.Prod_83_3689
PubMedID: 33320645

Title : Centella asiatica prevents D-galactose-Induced cognitive deficits, oxidative stress and neurodegeneration in the adult rat brain - Firdaus_2020_Drug.Chem.Toxicol__1
Author(s) : Firdaus Z , Singh N , Prajapati SK , Krishnamurthy S , Singh TD
Ref : Drug & Chemical Toxicology , :1 , 2020
Abstract : Chronic D-galactose (D-gal) administration causes cognitive impairment and is used widely in animal models for anti-aging studies. Centella asiatica (CA), a traditional herbal medicine, has been used as a brain tonic to enhance memory. This study evaluates the neuroprotective role of an ethanolic extract of Centella asiatica (CAE) against D-gal-induced aging in rats. Healthy male rats were divided into three groups: Control, D-gal, and D-gal + CAE. The Control group received normal saline (i.p.), whereas the D-gal group received D-gal (120 mg/kg b.w., i.p.), and the D-gal + CAE group received D-gal (120 mg/kg b.w., i.p.) and CAE (300 mg/kg b.w., orally) daily for 42 days. Behavioral and brain biochemical and histopathological changes were assessed after treatment. The results of the behavioral study depicted that D-gal significantly reduces the spontaneous alternation and locomotor activity indicating behavioral and cognitive impairment. Biochemical studies showed that D-gal significantly increases the oxidative stress and acetylcholinesterase activity (AChE) in rat brain. Histopathological study showed that D-gal disturbs the normal architecture of hippocampal and cortical cells, indicating degeneration in these brain areas. D-gal and CAE co-treatment for 42 days attenuated the behavioral, biochemical, and neuroanatomical impairments caused by the D-gal; it markedly suppresses the D-gal-induced oxidative stress and AChE activity in the brain, and maintains the normal cellular architecture in hippocampal and cortical areas. Thus, this study shows that CAE can protect the brain from the adverse effects of D-gal (e.g., memory loss and cognitive impairment) by modulating AChE activity and oxidative stress.
ESTHER : Firdaus_2020_Drug.Chem.Toxicol__1
PubMedSearch : Firdaus_2020_Drug.Chem.Toxicol__1
PubMedID: 33078641

Title : Development of potent inhibitors of the human microsomal epoxide hydrolase - Barnych_2020_Eur.J.Med.Chem_193_112206
Author(s) : Barnych B , Singh N , Negrel S , Zhang Y , Magis D , Roux C , Hua X , Ding Z , Morisseau C , Tantillo DJ , Siegel JB , Hammock BD
Ref : Eur Journal of Medicinal Chemistry , 193 :112206 , 2020
Abstract : Microsomal epoxide hydrolase (mEH) hydrolyzes a wide range of epoxide containing molecules. Although involved in the metabolism of xenobiotics, recent studies associate mEH with the onset and development of certain disease conditions. This phenomenon is partially attributed to the significant role mEH plays in hydrolyzing endogenous lipid mediators, suggesting more complex and extensive physiological functions. In order to obtain pharmacological tools to further study the biology and therapeutic potential of this enzyme target, we describe the development of highly potent 2-alkylthio acetamide inhibitors of the human mEH with IC50 values in the low nanomolar range. These are around 2 orders of magnitude more potent than previously obtained primary amine, amide and urea-based mEH inhibitors. Experimental assay results and rationalization of binding through docking calculations of inhibitors to a mEH homology model indicate that an amide connected to an alkyl side chain and a benzyl-thio function as key pharmacophore units.
ESTHER : Barnych_2020_Eur.J.Med.Chem_193_112206
PubMedSearch : Barnych_2020_Eur.J.Med.Chem_193_112206
PubMedID: 32203787
Gene_locus related to this paper: human-EPHX1 , mouse-EPHX1

Title : Ameliorative Effect of Phosphodiesterase-5 Inhibitor in Rat Model of Vascular Dementia - Bhatia_2019_Curr.Neurovasc.Res_16_27
Author(s) : Bhatia P , Singh N
Ref : Curr Neurovasc Res , 16 :27 , 2019
Abstract : INTRODUCTION: Cerebral hypoperfusion has been considered as major risk factor for Vascular Dementia (VaD). The present study shows the potential of Tadalafil, a phosphodiesterase-5 inhibitor, in bilateral common carotid artery occlusion (BCCAo) induced VaD in rats. MATERIALS AND METHODS: BCCAo procedure was performed under anesthesia in wistar rats to induce VaD. Morris Water-Maze (MWM) parameter was employed on 7th day post-surgery to determine learning and memory. Escape latency time, time spent in target quadrant, Path length and average swim speed taken as important parameters in MWM. Endothelial dysfunction was assessed in isolated aorta by observing endothelial dependent vasorelaxations and levels of serum nitrite. Various biochemical and histopathological estimations were also performed. RESULTS: BCCAo produced significant impairment in endothelium dependent vasorelaxation and a decrease in serum nitrite levels indicating endothelial dysfunction. Further poor performance on MWM represents impairment of learning and memory. There was a significant rise in brain oxidative stress level (indicated by increase in brain thiobarbituric acid reactive species and decrease in reduced glutathione levels). Increase in brain acetylcholinesterase activity; brain myloperoxidase activity and brain neutrophil infiltration (as marker of inflammation) were also observed. Treatment of Tadalafil (5 & 10 mg/kg, p. o.)/Donepezil (0. 5 mg/kg, i.p., serving as standard) ameliorated BCCAo induced endothelial dysfunction; memory deficits; biochemical and histopathological changes in a significant manner. CONCLUSION: It may be concluded that Tadalafil has shown efficacy in rat model of BCCAo induced VaD and that phosphodiesterase-5 can be considered as an important therapeutic target for the treatment of VaD.
ESTHER : Bhatia_2019_Curr.Neurovasc.Res_16_27
PubMedSearch : Bhatia_2019_Curr.Neurovasc.Res_16_27
PubMedID: 30706814

Title : Metal-Organocatalyst for Detoxification of Phosphorothioate Pesticides: Demonstration of Acetylcholine Esterase Activity - Singh_2019_Inorg.Chem_58_9773
Author(s) : Singh A , Raj P , Dubowski JJ , Kaur N , Singh N
Ref : Inorg Chem , 58 :9773 , 2019
Abstract : In recent years, transition metal complexes have been developed for catalytical degradation of a phosphate ester bond, particularly in RNA and DNA; however, less consideration has been given for development of complexes for the degradation of a phosphorothioate bond, as they are the foremost used pesticides in the environment and are toxic to human beings. In this context, we have developed copper complexes of benzimidazolium based ligands for catalytical degradation of a series of organophosphates (parathion, paraoxon, methyl-parathion) at ambient conditions. The copper complexes (assigned as N1-N3) were characterized using single X-ray crystallography which revealed that all three complexes are mononuclear and distorted square planner in geometry. Further, the solution state studies of the prepared complexes were carried out using UV-visible absorption, fluorescence spectroscopy, and cyclic voltametry. The complexes N1 and N2 have benzimidazolium ionic liquid as base attached with two 2-mercapto-benzimidazole pods, whereas complex N3 contains a nonionic ligand. The synthesized copper complexes were evaluated for their catalytic activity for degradation of organophosphates. It is interesting that the complex containing the ionic ligand efficiently degrades phosphorothioate pesticides, whereas complex N3 was not found to be appropriate for degradation due to a weaker conversion rate. The organophosphate degradation studies were monitored by recording absorbance spectra of parathion in the presence of catalyst, i.e., copper complexes with respect to time. The parathion was hydrolyzed into para-nitrophenol and diethyl thiophosphate. Moreover, to analyze the inhibition activity of the pesticides toward acetylcholine esterase enzyme in the presence of prepared metal complexes, Ellman's assay was performed and revealed that, within 20 min, the inhibition of acetylcholine esterase enzyme decreases by up to 13%.
ESTHER : Singh_2019_Inorg.Chem_58_9773
PubMedSearch : Singh_2019_Inorg.Chem_58_9773
PubMedID: 31318533

Title : Calcineurin inhibitors improve memory loss and neuropathological changes in mouse model of dementia - Kumar_2017_Pharmacol.Biochem.Behav_153_147
Author(s) : Kumar A , Singh N
Ref : Pharmacol Biochem Behav , 153 :147 , 2017
Abstract : AIM: The present study was designed to investigate the potential of Cyclosporine (CsA) and Tacrolimus, the inhibitors of calcineurin (CaN) in cognitive deficits of mice.
METHODS: Streptozotocin [STZ, 3mg/kg, injected intracerebroventricular (i.c.v.)] was used to induce memory deficits in NIH mice, while aged mice separately taken served as a natural model of dementia. Morris water maze (MWM) test was employed to evaluate learning and memory of the animals. A battery of biochemical and histopathological studies was also performed. Extent of oxidative stress was measured by estimating the levels of brain glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity was estimated to assess cholinergic activity. The brain level of myeloperoxidase (MPO) was measured as a marker of inflammation.
RESULTS: STZ i.c.v. and aging results in marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ i.c.v. treated mice and aged mice exhibited a marked accentuation of AChE activity, TBARS and MPO levels along with a fall in GSH level. Further the stained micrographs of STZ treated mice and aged mice indicate pathological changes, severe neutrophilic infiltration and amyloid deposition. Cyclosporine and Tacrolimus treatment significantly attenuated STZ induced and age related memory deficits, biochemical and histopathological alterations. CONCLUSION: The findings demonstrate the potential of CaN inhibitors Cyclosporine and Tacrolimus in memory dysfunctions which may probably be attributed to anti-cholinesterase, anti-amyloid, anti-oxidative and anti-inflammatory effects. It is concluded that CaN can be explored as a potential therapeutic target in dementia.
ESTHER : Kumar_2017_Pharmacol.Biochem.Behav_153_147
PubMedSearch : Kumar_2017_Pharmacol.Biochem.Behav_153_147
PubMedID: 28063945

Title : De Novo Genome and Transcriptome Assembly of the Canadian Beaver (Castor canadensis) - Lok_2017_G3.(Bethesda)_7_755
Author(s) : Lok S , Paton TA , Wang Z , Kaur G , Walker S , Yuen RK , Sung WW , Whitney J , Buchanan JA , Trost B , Singh N , Apresto B , Chen N , Coole M , Dawson TJ , Ho K , Hu Z , Pullenayegum S , Samler K , Shipstone A , Tsoi F , Wang T , Pereira SL , Rostami P , Ryan CA , Tong AH , Ng K , Sundaravadanam Y , Simpson JT , Lim BK , Engstrom MD , Dutton CJ , Kerr KC , Franke M , Rapley W , Wintle RF , Scherer SW
Ref : G3 (Bethesda) , 7 :755 , 2017
Abstract : The Canadian beaver (Castor canadensis) is the largest indigenous rodent in North America. We report a draft annotated assembly of the beaver genome, the first for a large rodent and the first mammalian genome assembled directly from uncorrected and moderate coverage (< 30 x) long reads generated by single-molecule sequencing. The genome size is 2.7 Gb estimated by k-mer analysis. We assembled the beaver genome using the new Canu assembler optimized for noisy reads. The resulting assembly was refined using Pilon supported by short reads (80 x) and checked for accuracy by congruency against an independent short read assembly. We scaffolded the assembly using the exon-gene models derived from 9805 full-length open reading frames (FL-ORFs) constructed from the beaver leukocyte and muscle transcriptomes. The final assembly comprised 22,515 contigs with an N50 of 278,680 bp and an N50-scaffold of 317,558 bp. Maximum contig and scaffold lengths were 3.3 and 4.2 Mb, respectively, with a combined scaffold length representing 92% of the estimated genome size. The completeness and accuracy of the scaffold assembly was demonstrated by the precise exon placement for 91.1% of the 9805 assembled FL-ORFs and 83.1% of the BUSCO (Benchmarking Universal Single-Copy Orthologs) gene set used to assess the quality of genome assemblies. Well-represented were genes involved in dentition and enamel deposition, defining characteristics of rodents with which the beaver is well-endowed. The study provides insights for genome assembly and an important genomics resource for Castoridae and rodent evolutionary biology.
ESTHER : Lok_2017_G3.(Bethesda)_7_755
PubMedSearch : Lok_2017_G3.(Bethesda)_7_755
PubMedID: 28087693
Gene_locus related to this paper: cascn-a0a250y2s0 , cascn-a0a250y135 , cascn-a0a250y1i6 , cascn-a0a250y2u8 , cascn-a0a250xy53 , ursma-a0a384cw87 , cascn-a0a250y6h8

Title : Pharmacological activation of protein kinase A improves memory loss and neuropathological changes in a mouse model of dementia of Alzheimer's type - Kumar_2017_Behav.Pharmacol_28_187
Author(s) : Kumar A , Singh N
Ref : Behav Pharmacol , 28 :187 , 2017
Abstract : The study investigates the therapeutic potential of the protein kinase A (PKA) activator forskolin in cognitive deficits of mice. Streptozotocin (STZ) [3 mg/kg, intracerebroventricularly (i.c.v.)] was used to induce memory deficits in mice, whereas aged mice served as natural model of dementia. Forskolin (2.5, 5, and 10 mg/kg/day, oral) treatment was administered to i.c.v. STZ-treated and aged mice for 14 days. The Morris Water Maze test was used to evaluate learning and memory. Estimation of brain acetylcholinesterase (AChE) activity, brain glutathione, thiobarbituric acid-reactive species, brain myeloperoxidase levels, and histopathological studies were also performed. Both STZ i.c.v. and aging resulted in a marked decline in Morris Water Maze performance, reflecting impairment of learning and memory. STZ i.c.v.-treated mice and aged mice showed a marked accentuation of AChE activity, thiobarbituric acid-reactive species and myeloperoxidase levels along with a decrease in the glutathione level. Further, the stained micrographs of STZ-treated mice and aged mice indicated pathological changes, severe neutrophilic infiltration, and amyloid deposition. Forskolin treatment significantly attenuated STZ-induced and age-related memory deficits, and biochemical and histopathological alterations. The findings indicate that the PKA activator forskolin probably alleviated memory deficits by virtue of its anticholinesterase, antiamyloid, antioxidative, and anti-inflammatory effects. It is concluded that PKA could be explored as a potential therapeutic target in dementia.
ESTHER : Kumar_2017_Behav.Pharmacol_28_187
PubMedSearch : Kumar_2017_Behav.Pharmacol_28_187
PubMedID: 28177982

Title : Exploration of multi-target potential of chromen-4-one based compounds in Alzheimer's disease: Design, synthesis and biological evaluations - Singh_2017_Bioorg.Med.Chem_25_6273
Author(s) : Singh M , Kaur M , Singh N , Silakari O
Ref : Bioorganic & Medicinal Chemistry , 25 :6273 , 2017
Abstract : A novel series of flavonoid based compounds were designed, synthesized and biologically evaluated for Acetylcholinesterase (AChE) inhibitory activity integrated with advanced glycation end products (AGEs) inhibitory and antioxidant potential. Most of the derivatives inhibited AChE in nanomolar IC50 range along with good AGEs inhibitory and radical scavenging activity. Among them, 7m, strongly inhibited AChE (IC50=5.87nM) and found to be potent as compared to the reference drug donepezil (IC50=12.7nM). Its potent inhibitory activity has been justified by docking analysis that revealed its dual binding characteristic with both CAS (catalytic active site) and PAS (peripheral anionic site) of AChE, simultaneously. Additionally, this compound also displayed ability to prevent advanced glycation end products formation (IC50=23.0microM) with additional radical scavenging property (IC50=37.12nM). It (7m) also ameliorated scopolamine induced memory deficit in mice employing Morris water maze test. Thus, flavonoids might be the promising lead compounds as potential polyfunctional anti-Alzheimer's agents.
ESTHER : Singh_2017_Bioorg.Med.Chem_25_6273
PubMedSearch : Singh_2017_Bioorg.Med.Chem_25_6273
PubMedID: 29089261

Title : Biodegradation of phthalic acid esters (PAEs) and in silico structural characterization of mono-2-ethylhexyl phthalate (MEHP) hydrolase on the basis of close structural homolog - Singh_2017_J.Hazard.Mater_338_11
Author(s) : Singh N , Dalal V , Mahto JK , Kumar P
Ref : J Hazard Mater , 338 :11 , 2017
Abstract : Three bacterial strains capable of degrading phthalates namely Pseudomonas sp. PKDM2, Pseudomonas sp. PKDE1 and Pseudomonas sp. PKDE2 were isolated and characterized for their degradative potential. These strains efficiently degraded 77.4%-84.4% of DMP, 75.0%-75.7% of DEP and 71.7%-74.7% of DEHP, initial amount of each phthalate is 500mgL(-1) of each phthalate, after 44h of incubation. GC-MS results reveal the tentative DEHP degradation pathway, where hydrolases mediate the breakdown of DEHP to phthalic acid (PA) via an intermediate MEHP. MEHP hydrolase is a serine hydrolase which is involved in the reduction of the MEHP to PA. The predicted 3D model of MEHP hydrolase from Pseudomonas mosselii was docked with phthalate monoesters (PMEs) such as MEHP, mono-n-hexyl phthalate (MHP), mono-n-butyl phthalate (MBP) and mono-n-ethyl phthalate (MEP), respectively. Docking results show the distance between the carbonyl carbon of respective phthalate monoester and the hydroxyl group of catalytic serine lies in the range of 2.9 to 3.3A, which is similar to the ES complex of other serine hydrolases. This structural study highlights the interaction and the role of catalytic residues of MEHP hydrolase involved in the biodegradation of PMEs to phthalate.
ESTHER : Singh_2017_J.Hazard.Mater_338_11
PubMedSearch : Singh_2017_J.Hazard.Mater_338_11
PubMedID: 28531656
Gene_locus related to this paper: 9psed-a0a1h9kym9

Title : Inhibitor of Phosphodiestearse-4 improves memory deficits, oxidative stress, neuroinflammation and neuropathological alterations in mouse models of dementia of Alzheimer's Type - Kumar_2017_Biomed.Pharmacother_88_698
Author(s) : Kumar A , Singh N
Ref : Biomed Pharmacother , 88 :698 , 2017
Abstract : The study investigates the potential of Rolipram a phosphodiesterase-4 inhibitor in cognitive deficits induced by streptozotocin (STZ, 3mg/kg intracerebroventricularly) and natural ageing in mice. Morris water maze (MWM) test was employed to evaluate learning and memory of the animals. Extent of oxidative stress was measured by estimating the levels of brain glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity was also estimated. The brain activity of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ and ageing results in marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ treated mice and aged mice exhibited a marked accentuation of AChE activity, TBARS and MPO activity along with fall in GSH level. Further the stained micrographs of STZ treated mice and aged mice indicate pathological changes, severe neutrophilic infiltration and amyloid deposition. Rolipram treatment significantly attenuated STZ induced and age related memory deficits, biochemical and histopathological alterations. The findings demonstrate the potential of Rolipram in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-amyloid, anti-oxidative and anti-inflammatory effects. The study concludes that PDE-4 can be explored as a potential therapeutic target in dementia.
ESTHER : Kumar_2017_Biomed.Pharmacother_88_698
PubMedSearch : Kumar_2017_Biomed.Pharmacother_88_698
PubMedID: 28152479

Title : Progress in drug development for Alzheimer's disease: An overview in relation to mitochondrial energy metabolism - Hroudova_2016_Eur.J.Med.Chem_121_774
Author(s) : Hroudova J , Singh N , Fisar Z , Ghosh KK
Ref : Eur Journal of Medicinal Chemistry , 121 :774 , 2016
Abstract : Current possibilities of Alzheimer's disease (AD) treatment are very limited and are based on administration of cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or N-methyl-d-aspartate receptor antagonist, memantine. Newly synthesized drugs affect multiple AD pathophysiological pathways and can act as inhibitors of cholinesterases (AChE, BuChE), inhibitors of monoamine oxidases (MAO-A, MAO-B), modulators of mitochondrial permeability transition pores, modulators of amyloid-beta binding alcohol dehydrogenase and antioxidants. Effects of clinically used as well as newly developed AD drugs were studied in relation to energy metabolism and mitochondrial functions, including oxidative phosphorylation, activities of enzymes of citric acid cycle or electron transfer system, mitochondrial membrane potential, calcium homeostasis, production of reactive oxygen species and MAO activity.
ESTHER : Hroudova_2016_Eur.J.Med.Chem_121_774
PubMedSearch : Hroudova_2016_Eur.J.Med.Chem_121_774
PubMedID: 27094132

Title : Effect of homeopathic Lycopodium clavatum on memory functions and cerebral blood flow in memory-impaired rats - Hanif_2015_Homeopathy_104_24
Author(s) : Hanif K , Kumar M , Singh N , Shukla R
Ref : Homeopathy , 104 :24 , 2015
Abstract : BACKGROUND: Lycopodium clavatum (Lyc) is a widely used homeopathic medicine for the liver, urinary and digestive disorders. Recently, acetyl cholinesterase (AchE) inhibitory activity has been found in Lyc alkaloid extract, which could be beneficial in dementia disorder. However, the effect of Lyc has not yet been explored in animal model of memory impairment and on cerebral blood flow. AIM: The present study was planned to explore the effect of Lyc on learning and memory function and cerebral blood flow (CBF) in intracerebroventricularly (ICV) administered streptozotocin (STZ) induced memory impairment in rats. MATERIALS AND
METHODS: Memory deficit was induced by ICV administration of STZ (3 mg/kg) in rats on 1st and 3rd day. Male SD rats were treated with Lyc Mother Tincture (MT) 30, 200 and 1000 for 17 days. Learning and memory was evaluated by Morris water maze test on 14th, 15th and 16th day. CBF was measured by Laser Doppler flow meter on 17th day.
RESULTS: STZ (ICV) treated rats showed impairment in learning and memory along with reduced CBF. Lyc MT and 200 showed improvement in learning and memory. There was increased CBF in STZ (ICV) treated rats at all the potencies of Lyc studied. CONCLUSION: The above study suggests that Lyc may be used as a drug of choice in condition of memory impairment due to its beneficial effect on CBF.
ESTHER : Hanif_2015_Homeopathy_104_24
PubMedSearch : Hanif_2015_Homeopathy_104_24
PubMedID: 25576268

Title : Insight into the esterase like activity demonstrated by an imidazole appended self-assembling hydrogelator - Singh_2015_Chem.Commun.(Camb)_51_13213
Author(s) : Singh N , Conte MP , Ulijn RV , Miravet JF , Escuder B
Ref : Chem Commun (Camb) , 51 :13213 , 2015
Abstract : A low molecular weight hydrogelator with a covalently appended imidazole moiety is reported. Capable of percolating water in the pH range of 6 to 8, it proves to be an efficient catalyst upon self-assembly, showing Michaelis-Menten type kinetics. Activities at different pH values correlated with dramatic structural changes were observed. It can hydrolyse p-nitrophenyl acetate (pNPA) as well as inactivated esters, and l and d-phenylalanine methyl esters. The enhanced activity can be related to the conglomeration of catalytic groups upon aggregation resulting in their close proximity and the formation of hydrophobic pockets.
ESTHER : Singh_2015_Chem.Commun.(Camb)_51_13213
PubMedSearch : Singh_2015_Chem.Commun.(Camb)_51_13213
PubMedID: 26194473

Title : Efficacy of Cilostazol a selective phosphodiesterase-3 inhibitor in rat model of Streptozotocin diabetes induced vascular dementia - Kumar_2015_Pharmacol.Biochem.Behav_135_20
Author(s) : Kumar A , Jaggi AS , Singh N
Ref : Pharmacol Biochem Behav , 135 :20 , 2015
Abstract : The present study has been designed to investigate the potential of Cilostazol a phosphodiesterase-3 (PDE-3) inhibitor in diabetes-induced vascular dementia (Vad) employing Wistar rats. A single dose of Streptozotocin (STZ) was used for the induction of diabetes and subsequent Vad in rats. Memory and learning abilities of rats were evaluated with Morris water maze (MWM) test. Serum glucose, body weight, vascular endothelial function, serum nitrite/nitrate levels, brain oxidative stress levels (viz. brain thiobarbituric acid reactive species and reduced glutathione levels), inflammatory markers (viz. brain myeloperoxidase activity and neutrophil infiltration in the brain hippocampal area) and brain acetylcholinesterase activity were also tested. Donepezil was used as positive control. Streptozotocin treated animals showed poor performance on MWM indicating impairment of learning and memory abilities with a significant reduction in body weight, vascular endothelial function, serum nitrite/nitrate levels, along with an increase in serum glucose, brain oxidative stress levels, inflammatory changes and brain acetylcholinesterase activity. Treatment with selective PDE-3 inhibitor, Cilostazol significantly attenuated, diabetes-induced impairment of learning and memory; endothelial dysfunction, and changes in various biochemical parameters. It is concluded that selective PDE-3 inhibitor, Cilostazol may be considered as the potential pharmacological agent for the management of diabetes-induced vascular dementia.
ESTHER : Kumar_2015_Pharmacol.Biochem.Behav_135_20
PubMedSearch : Kumar_2015_Pharmacol.Biochem.Behav_135_20
PubMedID: 25987325

Title : Development and Structural Modifications of Cholinesterase Reactivators against Chemical Warfare Agents in Last Decade: A Review - Sharma_2015_Mini.Rev.Med.Chem_15_58
Author(s) : Sharma R , Gupta B , Singh N , Acharya JR , Musilek K , Kuca K , Ghosh KK
Ref : Mini Rev Med Chem , 15 :58 , 2015
Abstract : Organophosphate (OP) pesticides and nerve agents are responsible for suicidal and accidental poisonings. The acute toxicity of nerve agents leads to progressive inhibition of the enzyme acetylcholinesterase (AChE) by phosphylation of serine residue at the active site of gorge. The recent massive destruction of Syrian civilians by nerve gas sarin, has again renewed the research attention of global science fraternity towards nerve agents, their mode of action and most prominently their therapeutic treatment. This review is principally focused on nerve agent intoxication. The common approach to deal with OP-intoxication is, application of antimuscarinic drug (atropine), anticonvulsant drug (diazepam) and clinically used oximes (pralidoxime, trimedoxime, obidoxime and asoxime). However, the existing therapeutic approach is arguable and has several failings to cure all kinds of nerve agent poisonings. Considering this issue, numerous oximes have been synthesized and screened through various in-vitro and in-vivo studies in last decade to overcome the downsides. At present, only a few oximes (bis pyridinum-oximes) exhibit sound efficacy against selective OPs. In spite of extensive efforts, till date no oxime is available as a universal antidote against all the classes of OPs. This review is centered on the recent developments and structural modification of AChE reactivators against nerve agent toxicity. In particular, a deeper look has been taken into chemical modifications of the reactivators by incorporation of different structural moieties targeted towards the increased reactivation affinity and improved blood brain barrier (BBB) penetration.
ESTHER : Sharma_2015_Mini.Rev.Med.Chem_15_58
PubMedSearch : Sharma_2015_Mini.Rev.Med.Chem_15_58
PubMedID: 25441834

Title : From alpha-nucleophiles to functionalized aggregates: exploring the reactivity of hydroxamate ion towards esterolytic reactions in micelles - Singh_2015_Org.Biomol.Chem_13_2827
Author(s) : Singh N , Karpichev Y , Sharma R , Gupta B , Sahu AK , Satnami ML , Ghosh KK
Ref : Org Biomol Chem , 13 :2827 , 2015
Abstract : Owing to the rising threats of neurotoxic organophosphosphorus compounds, facile and efficient decontamination systems are required. Since the last few decades, the search for promising alpha-nucleophiles for straightforward and eco-friendly decontamination reactions using alpha-nucleophiles has been considerably boosted up. Among these, hydroxamic acids have been widely studied due to their potential alpha-nucleophilicity towards carbon and phosphorus based esters. This account summarizes our research on alpha-nucleophilicity of hydroxamate ions in water and micelles towards esterolytic reactions. Efforts of our group in the last few years have been collectively judged and compared with the crucial findings of researchers in the relevant field. The present article sheds light on the rich chemistry of the hydroxamate ion as a perfect candidate to degrade organophosphorus esters (i.e. nerve agents, pesticides and their simulants) in water, in micelles of conventional surfactants, and in functionalized micelles. The current report also provides an insight into the possible nature and mechanisms of these reactions. A brief account of the biological activities of hydroxamic acids that have recently spurred research in medicine against some fatal diseases has been included.
ESTHER : Singh_2015_Org.Biomol.Chem_13_2827
PubMedSearch : Singh_2015_Org.Biomol.Chem_13_2827
PubMedID: 25597899

Title : Evolving possible link between PI3K and NO pathways in neuroprotective mechanism of ischemic postconditioning in mice - Gulati_2014_Mol.Cell.Biochem_397_255
Author(s) : Gulati P , Singh N
Ref : Molecular & Cellular Biochemistry , 397 :255 , 2014
Abstract : The present study was conducted to pharmacologically investigate the influence of NO signaling pathway in PI3K mediated neuroprotective mechanism of ischemic postconditioning (iPoCo). Bilateral carotid artery occlusion (BCAO) of 12 min followed by reperfusion for 24 h was employed to produce ischemia/reperfusion-induced cerebral injury in male Swiss mice. Memory was assessed using Morris water maze test. Degree of motor incoordination was evaluated using inclined beam walk test, rotarod test, and lateral push test. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Brain acetylcholinesterase activity, thiobarbituric acid reactive species (TBARS), nitrite/nitrate and reduced glutathione (GSH) levels were also estimated. BCAO followed by reperfusion produced significant rise in cerebral infarct size, acetylcholinesterase activity, and TBARS levels along with fall in nitrite/nitrate and GSH levels. A significant impairment of memory and motor coordination was also noted. iPoCo consisting of three episodes of 10 s carotid artery occlusion and reperfusion significantly attenuated infarct size, memory impairment, motor incoordination, and altered biochemicals. iPoCo-induced neuroprotective effects were significantly abolished by wortmannin (a selective PI3K inhibitor). However, administration of L-Arginine (a NO precursor) in the presence of wortmannin restored the protective effect of ischemic postconditioning. It may be concluded that neuroprotective mechanism of iPoCo involves PI3K-mediated pathway with NO signaling as an important downstream step.
ESTHER : Gulati_2014_Mol.Cell.Biochem_397_255
PubMedSearch : Gulati_2014_Mol.Cell.Biochem_397_255
PubMedID: 25151147

Title : Liver X receptor agonist T0901317 reduces neuropathological changes and improves memory in mouse models of experimental dementia - Sodhi_2014_Eur.J.Pharmacol_732C_50
Author(s) : Sodhi RK , Singh N
Ref : European Journal of Pharmacology , 732C :50 , 2014
Abstract : The present study has been undertaken to explore the potential of liver X receptor (LXR) modulator, T0901317, in dementia induced by streptozotocin (STZ) and cholesterol enriched diet. Streptozotocin [STZ, 3mg/kg, injected intracerebroventricular (i.c.v.)] and high fat diet (HFD, administered for 90 days) were used to induce dementia in separate groups of Swiss albino mice. The Morris water maze (MWM) test was used to evaluate the effect on cognitive functions. Brain homogenate was used to perform a series of biochemical studies such as, estimation of brain reduced glutathione (GSH), thiobarbituric acid reactive species (TBARS), acetylcholinestrase (AChE) activity and myeloperoxidase (MPO) levels. Serum cholesterol was also determined. STZ and HFD produced a significant decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ/HFD treated mice exhibited a noticeable accentuation of AChE activity, TBARS and MPO levels along with reduction in GSH level. Further the stained micrographs of STZ/HFD treated mice indicated pathological changes, severe neutrophilic infiltration and amyloid deposition. T0901317 treatment significantly attenuated STZ and HFD-induced memory deficits, biochemical and histopathological alterations as well as HFD induced rise in cholesterol content. Hence the study indicates the potential role of liver X receptors in the pathophysiology of dementia. Therefore, the results demonstrate the defensive role of T0901317 in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-oxidative, anti-inflammatory and cholesterol lowering effects.
ESTHER : Sodhi_2014_Eur.J.Pharmacol_732C_50
PubMedSearch : Sodhi_2014_Eur.J.Pharmacol_732C_50
PubMedID: 24690259

Title : Neuroprotective effect of tadalafil, a PDE-5 inhibitor, and its modulation by L-NAME in mouse model of ischemia-reperfusion injury - Gulati_2014_J.Surg.Res_186_475
Author(s) : Gulati P , Singh N
Ref : J Surg Res , 186 :475 , 2014
Abstract : BACKGROUND: The present study investigates the neuroprotective effect of tadalafil, a selective phosphodiesterase-5 inhibitor, in a mouse model of ischemia-reperfusion injury. MATERIALS AND
METHODS: Bilateral carotid artery occlusion for 12 min followed by reperfusion for 24 h was employed to produce ischemia-reperfusion-induced cerebral injury in male Swiss mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was assessed using Morris water maze test. Degree of motor incoordination was evaluated using inclined beam walk test, rota-rod test, and lateral push test. Brain nitrite/nitrate, brain acetylcholinesterase activity, brain thiobarbituric acid reactive species, and glutathione levels were also estimated.
RESULTS: Bilateral carotid artery occlusion, followed by reperfusion, produced a significant rise in cerebral infarct size, brain nitrite/nitrate levels, acetylcholinesterase activity, and thiobarbituric acid reactive species level along with a fall in glutathione. A significant impairment of memory and motor coordination was also noted. Pretreatment of tadalafil significantly attenuated the above effects of ischemia-reperfusion injury. Tadalafil-induced neuroprotective effects were significantly attenuated by administration of L-NAME, a nonselective nitric oxide synthase inhibitor.
CONCLUSIONS: Results indicate that tadalafil exerts neuroprotective effects, probably through nitric oxide-dependent pathways. Therefore, phosphodiesterase-5 can be explored as an important target to contain ischemia-reperfusion injury.
ESTHER : Gulati_2014_J.Surg.Res_186_475
PubMedSearch : Gulati_2014_J.Surg.Res_186_475
PubMedID: 24011921

Title : Ameliorative Effect of a Selective Endothelin ETA Receptor Antagonist in Rat Model of L-Methionine-induced Vascular Dementia - Mangat_2014_Korean.J.Physiol.Pharmacol_18_201
Author(s) : Mangat GS , Jaggi AS , Singh N
Ref : Korean Journal of Physiology Pharmacology , 18 :201 , 2014
Abstract : The present study was designed to investigate the efficacy of selective ETA receptor antagonist, ambrisentan on hyperhomocysteinemia-induced experimental vascular dementia. L-methionine was administered for 8 weeks to induce hyperhomocysteinemia and associated vascular dementia in male rats. Ambrisentan was administered to L-methionine-treated effect rats for 4 weeks (starting from 5(th) to 8(th) week of L-methionine treatment). On 52(nd) day onward, the animals were exposed to the Morris water maze (MWM) for testing their learning and memory abilities. Vascular endothelial function, serum nitrite/nitrate levels, brain thiobarbituric acid reactive species (TBARS), brain reduced glutathione (GSH) levels, and brain acetylcholinesterase (AChE) activity were also measured. L-methionine-treated animals showed significant learning and memory impairment, endothelial dysfunction, decrease in/serum nitrite/nitrate and brain GSH levels along with an increase in brain TBARS levels and AChE activity. Ambrisentan significantly improved hyperhomocysteinemia-induced impairment of learning, memory, endothelial dysfunction, and changes in various biochemical parameters. These effects were comparable to that of donepezil serving as positive control. It is concluded that ambrisentan, a selective ETA receptor antagonist may be considered as a potential pharmacological agent for the management of hyperhomocysteinemia-induced vascular dementia.
ESTHER : Mangat_2014_Korean.J.Physiol.Pharmacol_18_201
PubMedSearch : Mangat_2014_Korean.J.Physiol.Pharmacol_18_201
PubMedID: 24976759

Title : Tadalafil enhances the neuroprotective effects of ischemic postconditioning in mice, probably in a nitric oxide associated manner - Gulati_2014_Can.J.Physiol.Pharmacol_92_418
Author(s) : Gulati P , Singh N
Ref : Canadian Journal of Physiology & Pharmacology , 92 :418 , 2014
Abstract : This study investigates the modulatory effect of tadalafil, a selective phosphodiesterase (PDE-5) inhibitor, on the neuroprotective effects of ischemic postconditioning (iPoCo) in mice. Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 h was employed to produce ischemia and reperfusion induced cerebral injury. Cerebral infarct size was measured using TTC staining. Memory was assessed using the Morris water maze test. Degree of motor incoordination was evaluated using inclined beam-walking, rota-rod, and lateral push tests. Brain nitrite/nitrate, acetylcholinesterase activity, TBARS, and glutathione levels were also estimated. BCAO followed by reperfusion produced a significant increase in cerebral infarct size, brain nitrite/nitrate and TBARS levels, and acetylcholinesterase activity along with a reduction in glutathione. Marked impairment of memory and motor coordination was also noted. iPoCo consisting of 3 episodes of 10 s carotid artery occlusion and reperfusion instituted immediately after BCAO significantly decreased infarct size, memory impairment, motor incoordination, and altered biochemistry. Pretreatment with tadalafil mimicked the neuroprotective effects of iPoCo. The tadalafil-induced neuroprotective effects were significantly attenuated by l-NAME, a nonselective NOS inhibitor. We concluded that tadalafil mimics the neuroprotective effects of iPoCo, probably through a nitric oxide dependent pathway, and PDE-5 could be a target of interest with respect to the neuroprotective mechanism of iPoCo.
ESTHER : Gulati_2014_Can.J.Physiol.Pharmacol_92_418
PubMedSearch : Gulati_2014_Can.J.Physiol.Pharmacol_92_418
PubMedID: 24784472

Title : Neuroprotective mechanism of ischemic postconditioning in mice: a possible relationship between protein kinase C and nitric oxide pathways - Gulati_2014_J.Surg.Res_189_174
Author(s) : Gulati P , Singh N
Ref : J Surg Res , 189 :174 , 2014
Abstract : BACKGROUND: The present study was conducted to pharmacologically investigate the role of protein kinase C (PKC) pathway in neuroprotective mechanism of ischemic postconditioning (iPoCo) and determine the influence of nitric oxide (NO) signaling in PKC-mediated effects. MATERIALS AND
METHODS: Bilateral carotid artery occlusion of 12 min followed by reperfusion for 24 h was used to produce ischemia and reperfusion (I/R)-induced cerebral injury in male Swiss mice. Memory was assessed using Morris water maze test. Degree of motor incoordination was evaluated using inclined beam-walk test, rota-rod test, and lateral push test. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Brain acetylcholinesterase activity, thiobarbituric acid reactive species, nitrite/nitrate, and reduced glutathione levels were also estimated.
RESULTS: Bilateral carotid artery occlusion followed by reperfusion produced significant rise in cerebral infarct size, acetylcholinesterase activity, and thiobarbituric acid reactive species levels along with the fall in nitrite/nitrate and glutathione levels. A significant impairment of memory and motor coordination was also noted. iPoCo consisting of three episodes of 10 s carotid artery occlusion and reperfusion significantly attenuated infarct size, memory impairment, motor incoordination, and altered biochemicals. iPoCo-induced neuroprotective effects were significantly abolished by chelerythrine (a nonselective PKC inhibitor). l-Arginine, an NO precursor significantly attenuated I/R-induced injury and mimicked the neuroprotective effect of postconditioning. Furthermore, this protective effect of l-arginine on I/R injury and iPoCo was abolished when it was coadministered with chelerythrine.
CONCLUSIONS: It may be concluded that neuroprotective mechanism of iPoCo involves PKC mediated pathway with NO signaling as an essential step.
ESTHER : Gulati_2014_J.Surg.Res_189_174
PubMedSearch : Gulati_2014_J.Surg.Res_189_174
PubMedID: 24655662

Title : Pharmacological evidence for connection of nitric oxide-mediated pathways in neuroprotective mechanism of ischemic postconditioning in mice - Gulati_2014_J.Pharm.Bioallied.Sci_6_233
Author(s) : Gulati P , Singh N
Ref : J Pharm Bioallied Sci , 6 :233 , 2014
Abstract : INTRODUCTION: Postconditioning (PoCo) is an adaptive phenomenon whereby brief repetitive cycles of ischemia with intermittent reperfusion instituted immediately after prolonged ischemia at the onset of prolonged reperfusion elicit tissue protection. PoCo is noted to exert a protective effect in various organs like heart, liver, kidney and brain. Various triggers, mediators and end effectors are suggested to contribute to the protective effect of PoCo. However, the neuroprotective mechanism of PoCo is poorly understood. OBJECTIVES: The present study has been designed to investigate the role of nitric oxide pathway in the neuroprotective mechanism of ischemic postconditioning (iPoCo) employing a mouse model of global cerebral ischemia and reperfusion-induced injury. MATERIALS AND
METHODS: Bilateral carotid artery occlusion (BCAO) of 12 min followed by reperfusion for 24 h was employed to produce ischemia and reperfusion (I/R)-induced cerebral injury in mice. Cerebral injury was assessed in the terms of cerebral infarct, memory impairment and motor in-coordination. Brain nitrite/nitrate; acetylcholinesterase activity, thiobarbituric acid reactive species (TBARS) and glutathione level were also estimated.
RESULTS: BCAO followed by reperfusion produced a significant rise in cerebral infarct size, memory impairment and motor incoordination. Further a rise in acetylcholinesterase activity and TBARS level along with fall in brain nitrite/nitrate and glutathione levels was also noted. iPoCo consisting of three episodes of 10 s carotid artery occlusion and reperfusion (instituted immediately after BCAO) significantly attenuated infarct size, memory impairment, motor incoordination as well as altered biochemicals. iPoCo-induced neuroprotective effects were significantly abolished by pretreatment of L-NAME, a nonselective NOS inhibitor. CONCLUSION: It may be concluded that the nitric oxide pathway probably plays a vital role in the neuroprotective mechanism of iPoCo.
ESTHER : Gulati_2014_J.Pharm.Bioallied.Sci_6_233
PubMedSearch : Gulati_2014_J.Pharm.Bioallied.Sci_6_233
PubMedID: 25400405

Title : Pharmacologic evidence for role of endothelial nitric oxide synthase in neuroprotective mechanism of ischemic postconditioning in mice - Gulati_2014_J.Surg.Res_188_349
Author(s) : Gulati P , Singh N , Muthuraman A
Ref : J Surg Res , 188 :349 , 2014
Abstract : BACKGROUND: The present study was conducted to pharmacologically investigate the isoform-specific role of nitric oxide pathway in neuroprotective mechanism of ischemic postconditioning (iPoCo). MATERIALS AND
METHODS: Bilateral carotid artery occlusion of 12 min followed by reperfusion for 24 h was used to produce ischemia- and reperfusion-induced cerebral injury in male Swiss mice. Memory was assessed using Morris water maze test. Degree of motor in-coordination was evaluated using inclined beam-walk test, rotarod test, and lateral push test. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Brain acetylcholinestrase activity, thiobarbituric acid-reactive species, nitrite/nitrate, and reduced glutathione levels were also estimated. Western blotting was performed to determine endothelial nitric oxide synthase (eNOS) expression.
RESULTS: Bilateral carotid artery occlusion followed by reperfusion produced significant rise in cerebral infarct size, acetylcholinesterase activity, and thiobarbituric acid-reactive species levels along with fall in nitrite/nitrate, and glutathione and eNOS expression levels. A significant impairment of memory and motor coordination was also noted. iPoCo consisting of three episodes of 10-s carotid artery occlusion and reperfusion significantly attenuated infarct size, memory impairment, motor in-coordination, altered biochemicals, and protein expression levels. iPoCo-induced neuroprotective effects were significantly abolished by l-NAME (a nonselective nitric oxide synthase inhibitor) and l-NIO (a selective eNOS inhibitor). However, aminoguanidine (a selective inducible nitric oxide synthase inhibitor) and 7-nitroindazole (a selective neuronal nitric oxide synthase inhibitor) did not modulate beneficial effects of iPoCo.
CONCLUSIONS: It may be concluded that nitric oxide pathway probably plays a vital role with specific involvement of eNOS in neuroprotective mechanism of iPoCo.
ESTHER : Gulati_2014_J.Surg.Res_188_349
PubMedSearch : Gulati_2014_J.Surg.Res_188_349
PubMedID: 24439135

Title : Assessment of antidotal efficacy of cholinesterase reactivators against paraoxon: In vitro reactivation kinetics and physicochemical properties - Gupta_2014_Bioorg.Med.Chem.Lett_24_4743
Author(s) : Gupta B , Singh N , Sharma R , Foretic B , Musilek K , Kuca K , Acharya J , Satnami ML , Ghosh KK
Ref : Bioorganic & Medicinal Chemistry Lett , 24 :4743 , 2014
Abstract : The search of proficient oximes as reactivators of irreversibly inhibited-AChE by organophosphate poisoning necessitates an appropriate assessment of their physicochemical properties and reactivation kinetics. Therefore, herein acid dissociation constant; pKa, lipophilicity; logP, polar surface area, hydrogen bond donor and acceptor counts of structurally different oximes (two tertiary oximes and thirteen pyridinium aldoxime derivatives) have been evaluated. The experimentally obtained data for pKa has been comparatively analyzed by using non-linear regression. Further the tested oximes were screened through in vitro reactivation kinetics against paraoxon-inhibited AChE. The pKa values of all the examined oximes were within the range of 7.50-9.53. pKa values of uncharged and mono-pyridinium oximes were in good correlation with their reactivation potency. The high negative logP values of pyridinium oxime reactivators indicate their high hydrophilic character; hence oximes with improved lipophilicity should be designed for the development of novel and more potent antidotes. Propane and butane linked oximes were superior reactivators than xylene linked bis-oxime reactivators. It is concluded from the present study that pKa value is not only ruled by the position of oximino functionality in the pyridinium ring, but also by the position of linker. Although, pyridinium oximes are proved to be better reactivators but their lipophilicity has to be improved.
ESTHER : Gupta_2014_Bioorg.Med.Chem.Lett_24_4743
PubMedSearch : Gupta_2014_Bioorg.Med.Chem.Lett_24_4743
PubMedID: 25190468

Title : Efficacy of bosentan, a dual ET and ET endothelin receptor antagonist, in experimental diabetes induced vascular endothelial dysfunction and associated dementia in rats - Singh_2014_Pharmacol.Biochem.Behav_124C_27
Author(s) : Singh G , Sharma B , Jaggi AS , Singh N
Ref : Pharmacol Biochem Behav , 124C :27 , 2014
Abstract : The study was designed to investigate the efficacy of bosentan a dual endothelin (ETA and ETB) receptor antagonist in experimental diabetes induced vascular endothelial dysfunction and associated dementia. Diabetes was induced in rats by administration of a single dose (50mg/kg, i.p.) of streptozotocin (STZ). Drug treatment was started after 1month of STZ administration and treatment was continued until the end of the study. Morris water maze (MWM) test was employed for testing spatial learning and memory. Endothelial function was measured on isolated aortic rings using student physiograph. Serum glucose, body weight, serum nitrite/nitrate, brain thiobarbituric acid reactive species (TBARS), reduced glutathione (GSH) levels, and brain acetylcholinesterase activity were also tested. STZ treatment resulted in significant development of cognitive and vascular endothelial deficits, manifested in the terms of endothelial dysfunction, impairment of learning and memory, reduction in body weight and serum nitrite/nitrate levels along with increase in serum glucose, brain acetylcholinesterase activity, TBARS, and decreased GSH levels. Treatment of bosentan attenuated diabetes induced impairment of learning, memory, endothelial function, and various biochemical parameters. It may be concluded that bosentan has shown efficacy in STZ induced cognitive and vascular endothelial deficits. Thus, endothelin receptors can be considered as a potential pharmacological target for the management of experimental diabetes induced vascular endothelial dysfunction and associated dementia.
ESTHER : Singh_2014_Pharmacol.Biochem.Behav_124C_27
PubMedSearch : Singh_2014_Pharmacol.Biochem.Behav_124C_27
PubMedID: 24836182

Title : In vitro reactivation kinetics of paraoxon- and DFP-inhibited electric eel AChE using mono- and bis-pyridinium oximes - Gupta_2014_Arch.Toxicol_88_381
Author(s) : Gupta B , Sharma R , Singh N , Kuca K , Acharya JR , Ghosh KK
Ref : Archives of Toxicology , 88 :381 , 2014
Abstract : Oxime-assisted reactivation of organophosphate (OP)-inhibited acetylcholinesterase (AChE) is a crucial step in the post-inhibitory treatment of OP intoxication. The limited efficacy of oxime reactivators for all OP nerve agents and pesticides led to the development of various novel oximes and their thorough kinetic investigations. Hence, in the present investigation, we have tested 10 structurally different pyridinium oxime-based reactivators for their in vitro potency to reactivate paraoxon- and DFP-inhibited electric eel AChE. From structure activity relationship point of view, various oximes such as mono-quaternary (2-PAM, K100, K024) and bis-quaternary symmetric (obidoxime, TMB-4(Trimedoxime)) and asymmetric (K027, K048, K203, K618, K628) oximes bearing different connecting linkers (oxybismethylene, trimethylene, propane, butane, butene, and xylene) have been studied. The observed kinetic data demonstrate that not only the position of oxime group is decisive for the increased reactivation ability of oximes, but the role of connecting linker is also significant. Oximes with aliphatic linkers are superior reactivators than the oximes with unsaturated and aromatic linkers. The optimal chain length for plausible reactivation ability for paraoxon- and DFP-inhibited AChE is 3 or 4 carbon-carbon connecting linker between prydinium rings.
ESTHER : Gupta_2014_Arch.Toxicol_88_381
PubMedSearch : Gupta_2014_Arch.Toxicol_88_381
PubMedID: 24065055

Title : Attenuating effect of lisinopril and telmisartan in intracerebroventricular streptozotocin induced experimental dementia of Alzheimer's disease type: possible involvement of PPAR-gamma agonistic property - Singh_2013_J.Renin.Angiotensin.Aldosterone.Syst_14_124
Author(s) : Singh B , Sharma B , Jaggi AS , Singh N
Ref : J Renin Angiotensin Aldosterone Syst , 14 :124 , 2013
Abstract : This study investigates the beneficial role of lisinopril, an angiotensin converting enzyme inhibitor (ACEI) and telmisartan, an angiotensin receptor blocker (ARB), in intracerebroventricular (i.c.v.) streptozotocin (STZ) induced dementia of Alzheimer's disease (AD) type in mice. This study also aimed to explore the role of PPAR-gamma in lisinopril and telmisartan mediated effects in i.c.v. STZ mice. Donepezil served as the positive control in the study. Mice underwent i.c.v. injection of STZ. The Morris water maze (MWM) test was employed for assessment of learning and memory. Various biochemical estimations, namely brain acetylcholinesterase (AChE) activity, myeloperoxidase (MPO) activity, nitrite/nitrate and thiobarbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels, were also performed. The study showed that i.c.v. STZ significantly impaired learning and memory of the animals along with a significant enhancement in brain AChE, MPO, TBARS, nitrite/nitrate levels and reduction in brain GSH levels. Treatments of lisinopril/telmisartan/donepezil significantly attenuated STZ induced behavioral and biochemical changes. Pre-treatment with bisphenol-A-diglycidyl ether (BADGE), a selective PPAR-gamma antagonist, significantly abolished the beneficial effect of lisinopril/telmisartan in i.c.v. STZ treated animals. The results of this investigation document a potential role of PPAR-gamma in the beneficial effects of lisinopril and telmisartan in i.c.v. STZ dementia of AD type.
ESTHER : Singh_2013_J.Renin.Angiotensin.Aldosterone.Syst_14_124
PubMedSearch : Singh_2013_J.Renin.Angiotensin.Aldosterone.Syst_14_124
PubMedID: 23060470

Title : Physicochemical properties and supernucleophilicity of oxime-functionalized surfactants: hydrolytic catalysts toward dephosphorylation of di- and triphosphate esters - Singh_2013_J.Phys.Chem.B_117_3806
Author(s) : Singh N , Karpichev Y , Gupta B , Satnami ML , Marek J , Kuca K , Ghosh KK
Ref : J Phys Chem B , 117 :3806 , 2013
Abstract : Aggregation and kinetic studies have been performed to understand the hydrolytic potencies of the series of oxime-functionalized surfactants, viz., 3- hydroxyiminomethyl-1-alkylpyridinium bromide (alkyl = CnH2n+1, n = 10, 12, 14, 16, 18) in the cleavage of phosphate esters, p-nitrophenyl diphenyl phosphate (PNPDPP) and bis(2,4-dinitrophenyl) phosphate (BNDPP), in mixed micelles with cetylpyridinium bromide (CPB). Micellization and surface properties of mixed micelles functional surfactants with CPB were studied by conductivity and surface tension measurements. Acid dissociation constants (pKa) were determined, the effect of functional surfactant alkyl chain length and pH on the observed rate constant (kobs) for phosphate ester cleavage has been discussed, and the effect of substrate on the supernucleophilicities of the studied oximes was monitored. Functionalized oxime-based surfactants were proved to be supernucleophiles to attack on the P horizontal lineO center of tri- and diphosphate esters. Oximes with hexadecyl alkyl chain length (3-C16) showed maximum micellar effect on the rate constants toward PNPDPP. Micellar effects were analyzed in terms of the pseudophase model.
ESTHER : Singh_2013_J.Phys.Chem.B_117_3806
PubMedSearch : Singh_2013_J.Phys.Chem.B_117_3806
PubMedID: 23480470

Title : All-trans retinoic acid rescues memory deficits and neuropathological changes in mouse model of streptozotocin-induced dementia of Alzheimer's type - Sodhi_2013_Prog.Neuropsychopharmacol.Biol.Psychiatry_40_38
Author(s) : Sodhi RK , Singh N
Ref : Prog Neuropsychopharmacol Biological Psychiatry , 40 :38 , 2013
Abstract : Recent studies have revealed that aberrant vitamin A signaling may lead to memory deficits in rodents. Present study investigates the potential of all-trans-retinoic acid (ATRA) an agonist at retinoid acid family of receptors, in cognitive dysfunctions associated with experimental dementia. Streptozotocin (STZ) [3 mg/kg, intracerebroventricularly (i.c.v)] was administered on alternate days (day 1 and day 3) to induce dementia in Swiss albino mice. STZ mice were administered ATRA (10 mg/kg; 20 mg/kg, p.o.) for a total of 19 days following second i.c.v injection of STZ [day 4 to day 22]. Morris water maze (MWM) test was performed on days 19, 20, 21, 22 and 23 to assess learning and memory of the animals. Following MWM test, the animals were sacrificed for biochemical and histopathological studies. Extent of oxidative stress was measured by estimating the levels of brain reduced glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity and serum cholesterol levels were also estimated. The brain level of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ produced a marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ treated mice showed marked accentuation of AChE activity, TBARS and MPO levels along with fall in GSH level. Further the stained micrographs of STZ-treated mice indicated pathological changes, severe neutrophilic infiltration and amyloid deposition. ATRA treatment significantly attenuated STZ-induced memory deficits, biochemical and histopathological alterations. The findings demonstrate that the memory restorative ability of ATRA may be attributed to its anti-cholinesterase, anti-oxidative and anti-inflammatory potential.
ESTHER : Sodhi_2013_Prog.Neuropsychopharmacol.Biol.Psychiatry_40_38
PubMedSearch : Sodhi_2013_Prog.Neuropsychopharmacol.Biol.Psychiatry_40_38
PubMedID: 23044340

Title : Defensive Effect of Lansoprazole in Dementia of AD Type in Mice Exposed to Streptozotocin and Cholesterol Enriched Diet - Sodhi_2013_PLoS.One_8_e70487
Author(s) : Sodhi RK , Singh N
Ref : PLoS ONE , 8 :e70487 , 2013
Abstract : The present study investigates the potential of lansoprazole (a proton pump inhibitor and agonist of liver x receptors) in experimental dementia of AD type. Streptozotocin [STZ, 3 mg/kg, injected intracerebroventricular (i.c.v), and high fat diet (HFD, administered for 90 days)] were used to induce dementia in separate groups of Swiss mice. Morris water maze (MWM) test was performed to assess learning and memory of the animals. A battery of biochemical and histopathological studies were also performed. Extent of oxidative stress was measured by estimating the levels of brain reduced glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity and serum cholesterol levels were also estimated. The brain level of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ and HFD produced a marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ/HFD treated mice exhibited a marked accentuation of AChE activity, TBARS and MPO levels along with a fall in GSH levels. Further, the stained micrographs of STZ/HFD treated mice indicated pathological changes, severe neutrophilic infiltration and amyloid deposition. Lansoprazole treatment significantly attenuated STZ and HFD -induced memory deficits, biochemical and histopathological alterations. It also prevented HFD-induced rise in the cholesterol level. Therefore, the findings demonstrate potential of lansoprazole in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-oxidative and anti-inflammatory effects. Moreover, both cholesterol-dependent as well as cholesterol-independent effects of lansoprazole appear to play a role. In addition study indicates the role of liver x receptors in dementia.
ESTHER : Sodhi_2013_PLoS.One_8_e70487
PubMedSearch : Sodhi_2013_PLoS.One_8_e70487
PubMedID: 23936214

Title : Neuroprotective effect of gadolinium: a stretch-activated calcium channel blocker in mouse model of ischemia-reperfusion injury - Gulati_2013_Naunyn.Schmiedebergs.Arch.Pharmacol_386_255
Author(s) : Gulati P , Muthuraman A , Jaggi AS , Singh N
Ref : Naunyn Schmiedebergs Arch Pharmacol , 386 :255 , 2013
Abstract : The present study was designed to investigate the potential of gadolinium, a stretch-activated calcium channel blocker in ischemic reperfusion (I/R)-induced brain injury in mice. Bilateral carotid artery occlusion of 12 min followed by reperfusion for 24 h was given to induce cerebral injury in male Swiss mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was assessed using Morris water maze test and motor incoordination was evaluated using rota-rod, lateral push, and inclined beam walking tests. In addition, total calcium, thiobarbituric acid reactive substance (TBARS), reduced glutathione (GSH), and acetylcholinesterase (AChE) activity were also estimated in brain tissue. I/R injury produced a significant increase in cerebral infarct size. A significant loss of memory along with impairment of motor performance was also noted. Furthermore, I/R injury also produced a significant increase in levels of TBARS, total calcium, AChE activity, and a decrease in GSH levels. Pretreatment of gadolinium significantly attenuated I/R-induced infarct size, behavioral and biochemical changes. On the basis of the present findings, we can suggest that opening of stretch-activated calcium channel may play a critical role in ischemic reperfusion-induced brain injury and that gadolinium has neuroprotective potential in I/R-induced injury.
ESTHER : Gulati_2013_Naunyn.Schmiedebergs.Arch.Pharmacol_386_255
PubMedSearch : Gulati_2013_Naunyn.Schmiedebergs.Arch.Pharmacol_386_255
PubMedID: 23229582

Title : Acetylcholinesterase from human erythrocytes membrane: a screen for evaluating the activity of some traditional plant extracts - Srivastava_2012_Cell.Mol.Biol.(Noisy-le-grand)_58_160
Author(s) : Srivastava N , Sharma RK , Singh N , Sharma B
Ref : Cellular & Molecular Biology (Noisy-le-grand) , 58 :160 , 2012
Abstract : The extraction of plant constituents is essential to isolate biologically active compounds and understanding their role in disease prevention, treatment and in knowing their toxic effects as well. However, meager information is available about the properties and biological activities of phytochemicals derived from certain plants found in Allahabad and adjoining areas. Keeping this information in view, we prepared aqueous extracts and determined their biochemical properties including their impact on the activity of human RBC's acetylcholinesterase (AChE). The UV—Visible spectrophotometric profiles of the aqueous extracts of different parts of the four plant species viz. Calotropis procera, Datura metal, Cannabis sativa, Argemone mexicana and Thevitia peruviana displayed two major peaks at 302 and 336 nm corresponding to the presence of different flavonoids in these preparations. These extracts indicated presence of protein in the range of 1.12 to 19.25mg/g wet weight of the plant tissues. The impact of different phytochemicals present in these extracts was studied on the activity of AChE isolated from human erythrocytes (RBCs). The extracts derived from Argemone mexicana and Datura metal exhibited strong AChE inhibitory potential, whereas others did not show significant inhibition even at higher concentrations. The results indicate that human RBC's can be used as a potential biomarker towards evaluation of the efficacy and toxic potential of varied plant extracts.
ESTHER : Srivastava_2012_Cell.Mol.Biol.(Noisy-le-grand)_58_160
PubMedSearch : Srivastava_2012_Cell.Mol.Biol.(Noisy-le-grand)_58_160
PubMedID: 23273207

Title : Defensive effect of natrium diethyldithiocarbamate trihydrate (NDDCT) and lisinopril in DOCA-salt hypertension-induced vascular dementia in rats - Sharma_2012_Psychopharmacology.(Berl)_223_307
Author(s) : Sharma B , Singh N
Ref : Psychopharmacology (Berl) , 223 :307 , 2012
Abstract : RATIONALE Vascular dementia and hypertension are increasing day by day with a high degree of co-occurrence Tremendous amount of research work is required so that new pharmacological agents may be identified for their appropriate therapeutic utility to combat different dementing disorders OBJECTIVES This study investigates the effect of natrium diethyldithiocarbamate trihydrate NDDCT a nuclear factor kappa-B NF-kappaB inhibitor as well as lisinopril an angiotensin converting enzyme ACE inhibitor on deoxycorticosterone acetate DOCA hypertension-induced vascular dementia in rats METHODS DOCA was used to induce hypertension and associated vascular dementia Morris water maze MWM was used for testing learning and memory Endothelial function was assessed by acetylcholine-induced endothelium-dependent relaxation of aortic strips Different biochemical estimations were used to assess oxidative stress aortic superoxide anion serum and brain thiobarbituric acid reactive species and brain glutathione nitric oxide levels serum nitrite/nitrate and cholinergic activity brain acetyl cholinesterase activity RESULTS DOCA treatment significantly raised the mean arterial blood pressure of rats and these hypertensive rats performed poorly on MWM reflecting impairment of learning and memory DOCA treatment also impaired vascular endothelial function and different biochemical parameters Treatments of NDDCT as well as lisinopril significantly attenuated DOCA hypertension-induced impairment of learning and memory endothelial dysfunction and changes in various biochemical levels CONCLUSIONS DOCA-salt hypertension induces vascular dementia in rats NF-kappaB as well as ACE inhibitors may be considered as potential pharmacological agents for the management of hypertension-induced vascular dementia.
ESTHER : Sharma_2012_Psychopharmacology.(Berl)_223_307
PubMedSearch : Sharma_2012_Psychopharmacology.(Berl)_223_307
PubMedID: 22526544

Title : Pharmacological inhibition of inducible nitric oxide synthase (iNOS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, convalesce behavior and biochemistry of hypertension induced vascular dementia in rats - Sharma_2012_Pharmacol.Biochem.Behav_103_821
Author(s) : Sharma B , Singh N
Ref : Pharmacol Biochem Behav , 103 :821 , 2012
Abstract : Cognitive disorders are likely to increase over the coming years (5-10). Vascular dementia (VaD) has heterogeneous pathology and is a challenge for clinicians. Current Alzheimer's disease drugs have had limited clinical efficacy in treating VaD and none have been approved by major regulatory authorities specifically for this disease. Role of iNOS and NADPH-oxidase has been reported in various pathological conditions but there role in hypertension (Hypt) induced VaD is still unclear. This research work investigates the salutiferous effect of aminoguanidine (AG), an iNOS inhibitor and 4'-hydroxy-3'-methoxyacetophenone (HMAP), a NADPH oxidase inhibitor in Hypt induced VaD in rats. Deoxycorticosterone acetate-salt (DOCA-S) hypertension has been used for development of VaD in rats. Morris water-maze was used for testing learning and memory. Vascular system assessment was done by testing endothelial function. Mean arterial blood pressure (MABP), oxidative stress [aortic superoxide anion, serum and brain thiobarbituric acid reactive species (TBARS) and brain glutathione (GSH)], nitric oxide levels (serum nitrite/nitrate) and cholinergic activity (brain acetyl cholinesterase activity-AChE) were also measured. DOCA-S treated rats have shown increased MABP with impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate & brain GSH levels along with increase in serum & brain TBARS, and brain AChE activity. AG as well as HMAP significantly convalesce Hypt induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that AG, an iNOS inhibitor and HMAP, a NADPH-oxidase inhibitor may be considered as potential agents for the management of Hypt induced VaD.
ESTHER : Sharma_2012_Pharmacol.Biochem.Behav_103_821
PubMedSearch : Sharma_2012_Pharmacol.Biochem.Behav_103_821
PubMedID: 23201648

Title : Experimental hypertension induced vascular dementia: pharmacological, biochemical and behavioral recuperation by angiotensin receptor blocker and acetylcholinesterase inhibitor - Sharma_2012_Pharmacol.Biochem.Behav_102_101
Author(s) : Sharma B , Singh N
Ref : Pharmacol Biochem Behav , 102 :101 , 2012
Abstract : Involvement of vascular pathology has been suggested in hypertension as well as vascular dementia (VaD), which also have a very high degree of co-occurrence in ageing population. We have recently reported that experimental diabetes as well as hyperhomocystenemia induces VaD. In the present research work, for the first time we are reporting the genesis of VaD by deoxycorticosterone acetate (DOCA)-salt induced experimental hypertension. Furthermore, we have also investigated the beneficial effect of telmisartan, an angiotensin II type 1 receptor blocker (ARB) and donepezil, an acetylcholinesterase inhibitor (AChEI), on DOCA-salt hypertension induced VaD in rats. DOCA-salt hypertensive rats performed poorly on Morris water maze, reflecting impairment in their learning and memory. Furthermore, DOCA-salt treatment has shown a significant impairment of vascular endothelial function (DOCA attenuated acetylcholine induced endothelium dependent relaxation), with a significant reduction in serum nitrite/nitrate levels, along with increased aortic, serum and brain oxidative stress levels (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and brain acetylcholinesterase activity. Treatments of telmisartan as well as donepezil significantly attenuated DOCA-salt hypertension induced learning and memory deficits, endothelial dysfunction, and changes in various biochemical parameters. It may be concluded that DOCA-salt hypertension induces VaD in rats. ARBs and AChEIs may be considered as potential pharmacological agents for the management of hypertension induced VaD.
ESTHER : Sharma_2012_Pharmacol.Biochem.Behav_102_101
PubMedSearch : Sharma_2012_Pharmacol.Biochem.Behav_102_101
PubMedID: 22507914

Title : Salutary effect of NFkappaB inhibitor and folacin in hyperhomocysteinemia-hyperlipidemia induced vascular dementia - Sharma_2012_Prog.Neuropsychopharmacol.Biol.Psychiatry_38_207
Author(s) : Sharma B , Singh N
Ref : Prog Neuropsychopharmacol Biological Psychiatry , 38 :207 , 2012
Abstract : Dementia of vascular origin or vascular dementia (VaD) is considered as the second commonest form of dementia after Alzheimer's disease (AD). In the last ten years various researchers have reported a strong association of hyperhomocysteinemia (HHcy), hyperlipidemia (HL) and dementia. This study investigates the salutary effect of natrium diethyl dithio carbamate trihydrate (NDDCT), a nuclear factor-kappaB (NF-kappaB) inhibitor as well as folacin (Vitamin-B(9)) in HHcy-HL induced VaD. l-methionone was used to induce HHcy-HL and associated VaD. Morris water-maze (MWM) was used for testing learning and memory. Vascular system assessment was done by testing endothelial function. Biochemical estimations were performed to assess HHcy (serum homocysteine), HL (serum cholesterol), oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species and brain glutathione), nitric oxide levels (serum nitrite/nitrate) and cholinergic activity (brain acetyl cholinesterase activity). L-methionine treated animals have shown HHcy-HL, endothelial dysfunction, impairment of learning, memory, reduction in serum nitrite/nitrate levels and brain glutathione (GSH) along with increase in serum and brain thiobarbituric acid reactive species (TBARS), and brain acetylcholinesterase activity. NDDCT, folacin and donepezil (positive control) significantly improved HHcy-HL induced impairment of learning, memory, endothelial dysfunction, and changes in various biochemical parameters. l-methionine induced HHcy-HL has caused VaD development in rats. NFkappa-B inhibitors and folacin may be considered as potential agents for the management of HHcy-HL induced VaD.
ESTHER : Sharma_2012_Prog.Neuropsychopharmacol.Biol.Psychiatry_38_207
PubMedSearch : Sharma_2012_Prog.Neuropsychopharmacol.Biol.Psychiatry_38_207
PubMedID: 22510463

Title : A review on coumarins as acetylcholinesterase inhibitors for Alzheimer's disease - Anand_2012_Bioorg.Med.Chem_20_1175
Author(s) : Anand P , Singh B , Singh N
Ref : Bioorganic & Medicinal Chemistry , 20 :1175 , 2012
Abstract : Acetylcholinesterase (AChE) enzyme inhibition is an important target for the management of Alzheimer disease (AD) and AChE inhibitors are the main stay drugs for its management. Coumarins are the phytochemicals with wide range of biological activities including AChE inhibition. The scientists have attempted to explore the coumarin template for synthesizing novel AChE inhibitors with additional pharmacological activities including decrease in beta-amyloid (Abeta) deposition and beta-secretase inhibition that are also important for AD management. Most of the designed schemes have involved incorporation of a catalytic site interacting moiety at 3- and 4-positions of the coumarin ring. The present review describes these differently synthesized coumarin derivatives as AChE inhibitors for management of AD.
ESTHER : Anand_2012_Bioorg.Med.Chem_20_1175
PubMedSearch : Anand_2012_Bioorg.Med.Chem_20_1175
PubMedID: 22257528

Title : Pharmacological investigation of memory restorative effect of riluzole in mice - Rinwa_2012_Indian.J.Pharmacol_44_366
Author(s) : Rinwa P , Jaggi AS , Singh N
Ref : Indian J Pharmacol , 44 :366 , 2012
Abstract : OBJECTIVE: Streptozotocin (STZ) and sodium nitrite (NaNO(2)) treatment have been positively correlated with higher incidence of memory loss and experimental dementia. The present study was designed to investigate the potential of the Riluzole, an inhibitor of glutamatergic neurotransmission and activator of TWIK-Related K(+) channels with incidences of memory deficits associated with dementia in mice. MATERIALS AND METHODS: Dementia was induced in Swiss albino mice by intracerebroventricular STZ (ICV) and by subcutaneous NaNO(2) in separate groups of animals. Morris water maze was employed to assess learning and memory of the animals. Biochemical analysis of brain homogenate was performed so as to assess brain acetyl cholinesterase (AChE) activity. Brain thiobarbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels were measured to assess total oxidative stress. RESULTS: Treatment of ICV STZ and NaNO(2) produced a significant decrease in water maze performance of mice hence reflecting loss of learning and memory. Furthermore, higher levels of brain AChE activity and oxidative stress were observed in these animals. Administration of riluzole (5 and 10 mg/kg intraperitoneally) successfully attenuated memory deficits as well as ICV STZ- and NaNO(2) -induced changes in the levels of brain AChE, TBARS, and GSH. CONCLUSION: The memory restorative effects of riluzole in dementia may involve its multiple functions including anti-oxidative and anticholinesterase properties.
ESTHER : Rinwa_2012_Indian.J.Pharmacol_44_366
PubMedSearch : Rinwa_2012_Indian.J.Pharmacol_44_366
PubMedID: 22701248

Title : Pharmacological investigations on potential of peroxisome proliferator-activated receptor-gamma agonists in hyperhomocysteinemia-induced vascular dementia in rats - Sain_2011_Neurosci_192_322
Author(s) : Sain H , Sharma B , Jaggi AS , Singh N
Ref : Neuroscience , 192 :322 , 2011
Abstract : The present study has been designed to investigate the potential of peroxisome proliferator-activated receptor-gamma ([PPAR]-gamma) agonists, pioglitazone, and rosiglitazone in hyperhomocysteinemia-induced vascular dementia of rats. l-methionine was administered for 8 weeks to induce hyperhomocysteinemia and associated vascular dementia. Pioglitazone and rosiglitazone were administered to l-methionine-treated rats for 4 weeks (starting from 5th to 8th weeks of methionine treatment). Donepezil served as a positive control in this study. On 52nd day onward, the animals were exposed to Morris water maze (MWM) for testing learning and memory abilities. Vascular endothelial function, serum nitrite/nitrate levels, brain thiobarbituric acid reactive species (TBARS), brain reduced glutathione (GSH) levels, and brain acetylcholinesterase (AChE) activity were also measured. l-methionine-treated animals have shown impairment of learning, memory, endothelial function, decrease in serum nitrite/nitrate levels, and brain GSH levels along with increase in brain TBARS levels and AChE activity. Pioglitazone, rosiglitazone, and donepezil significantly improved hyperhomocysteinemia-induced impairment of learning, memory, endothelial dysfunction, and changes in various biochemical parameters. It is concluded that pioglitazone and rosiglitazone may be considered as potential pharmacological agents for the management of hyperhomocysteinemia-induced vascular dementia.
ESTHER : Sain_2011_Neurosci_192_322
PubMedSearch : Sain_2011_Neurosci_192_322
PubMedID: 21777659

Title : Attenuation of vascular dementia by sodium butyrate in streptozotocin diabetic rats - Sharma_2011_Psychopharmacology.(Berl)_215_677
Author(s) : Sharma B , Singh N
Ref : Psychopharmacology (Berl) , 215 :677 , 2011
Abstract : RATIONALE: Vascular dementia is the second leading cause of dementia, which is strongly associated with diabetes. Diabetes and dementia have become a major public health concern worldwide. At this point of time, it is very important to find the possible pharmacological agents which may be useful in management and therapy of dementia including Alzheimer's disease, vascular dementia, etc. OBJECTIVES: To investigate the effect of sodium butyrate on streptozotocin (STZ) diabetes induced vascular dementia in rats. METHODS: Diabetes and subsequent endothelial dysfunction and dementia were induced in rats by administration of single dose of STZ. Drug treatment was started after 1 month of STZ administration and treatment was continued until the end of the study. Morris water maze (MWM) test was employed for testing learning and memory. Endothelial function was measured on isolated aortic rings using student physiograph. Serum glucose, body weight, serum nitrite/nitrate, aortic superoxide anion generation, brain thiobarbituric acid reactive species (TBARS), reduced glutathione (GSH) levels, and acetylcholinesterase activity were also tested. RESULTS: STZ treatment produced endothelial dysfunction, impairment of learning and memory, reduction in body weight and serum nitrite/nitrate, and increase in serum glucose, aortic and brain oxidative stress (increased superoxide anion, TBARS, and decreased GSH levels), and brain acetylcholinesterase activity. Treatment of sodium butyrate attenuated diabetes induced impairment of learning, memory, endothelial function, and various biochemical parameters. CONCLUSIONS: Sodium butyrate may be considered as potential pharmacological agent for the management of diabetes induced vascular dementia.
ESTHER : Sharma_2011_Psychopharmacology.(Berl)_215_677
PubMedSearch : Sharma_2011_Psychopharmacology.(Berl)_215_677
PubMedID: 21225418

Title : Behavioral and biochemical investigations to explore pharmacological potential of PPAR-gamma agonists in vascular dementia of diabetic rats - Sharma_2011_Pharmacol.Biochem.Behav_100_320
Author(s) : Sharma B , Singh N
Ref : Pharmacol Biochem Behav , 100 :320 , 2011
Abstract : Vascular dementia (VaD) is the second most common dementing illness. We have recently reported that diabetes induces VaD in rats. The present study has been designed to investigate the potential of peroxisome-proliferator-activated receptors-gamma (PPAR-gamma) agonists in diabetes induced VaD of Wistar Albino rats. The rats were administered, single dose of streptozotocin (STZ) for the induction of diabetes. Morris water-maze (MWM) test was employed for testing learning and memory. Serum glucose, bodyweight, vascular endothelial function, serum nitrite/nitrate levels, aortic and brain oxidative stress levels (viz. aortic superoxide anion levels, brain thiobarbituric acid reactive species and brain glutathione levels) and brain acetylcholinesterase activity were also tested. STZ treated animals performed poorly on MWM hence reflecting impairment of learning and memory behavior with a significant reduction in body weight, impairment of vascular endothelial function, and decrease in serum nitrite/nitrate levels, increase in serum glucose, aortic and brain oxidative stress levels and brain acetylcholinesterase activity. Treatment of PPAR-gamma agonists, pioglitazone as well as rosiglitazone significantly reversed, diabetes induced impairment of learning and memory behavior, endothelial function, and changes in various biochemical parameters. It is concluded that PPAR-gamma modulators pioglitazone and rosiglitazone may be considered as potential pharmacological agents for the management of diabetes induced VaD.
ESTHER : Sharma_2011_Pharmacol.Biochem.Behav_100_320
PubMedSearch : Sharma_2011_Pharmacol.Biochem.Behav_100_320
PubMedID: 21893084

Title : Involvement of PPAR-gamma in curcumin-mediated beneficial effects in experimental dementia - Rinwa_2010_Naunyn.Schmiedebergs.Arch.Pharmacol_381_529
Author(s) : Rinwa P , Kaur B , Jaggi AS , Singh N
Ref : Naunyn Schmiedebergs Arch Pharmacol , 381 :529 , 2010
Abstract : The present study was undertaken to investigate the possible mechanism of curcumin-mediated beneficial effects in memory deficits associated with experimental dementia. Dementia was induced in Swiss albino mice by administering streptozotocin (3 mg kg(-1)) intracerebroventricularly on first and third day. Morris water maze test was employed to assess learning and memory of the animals. Biochemical analysis of brain homogenate was performed to assess brain acetyl cholinesterase (AChE) activity and total oxidative stress. Streptozotocin (STZ) produced a significant decrease in water maze performance of mice indicative of impairment in spatial reference memory. Curcumin (20 mg/kg p.o. daily for 14 days) successfully attenuated STZ-induced memory deficits. Higher levels of brain AChE activity and oxidative stress were observed in STZ-treated animals, which were significantly attenuated by curcumin. Furthermore, the noted beneficial effect of curcumin on STZ-induced dementia was significantly abolished by pretreatment with PPAR-gamma receptor antagonist bisphenol-A-diglycidyl ether, i.e., BADGE (30 mg/kg intraperitoneally (i.p.)). It may be concluded that the beneficial effects of curcumin are mediated through the activation of PPAR-gamma receptors.
ESTHER : Rinwa_2010_Naunyn.Schmiedebergs.Arch.Pharmacol_381_529
PubMedSearch : Rinwa_2010_Naunyn.Schmiedebergs.Arch.Pharmacol_381_529
PubMedID: 20369229

Title : Pitavastatin and 4'-hydroxy-3'-methoxyacetophenone (HMAP) reduce cognitive dysfunction in vascular dementia during experimental diabetes - Sharma_2010_Curr.Neurovasc.Res_7_180
Author(s) : Sharma B , Singh N
Ref : Curr Neurovasc Res , 7 :180 , 2010
Abstract : Diabetes has been found to increase the probability of vascular dementia in humans. We have investigated the effect of 4'-hydroxy-3'-methoxyacetophenone (HMAP), a NADPH oxidase inhibitor and Pitavastatin, HMG Co-A reductase inhibitor, on Streptozotocin (STZ) diabetes induced vascular dementia in rats. Donepezil served as a positive control. The rats were administered with single dose of STZ for the induction of diabetes. Drug treatment was started after one month of STZ administration and treatment was continued till the end of the study (i.e. 56th day). On 52nd day onwards, the animals were exposed to Morris water-maze (MWM) for testing learning & memory. Serum glucose, bodyweight, vascular endothelial function, serum nitrite / nitrate levels, aortic & brain oxidative stress levels and brain acetylcholinesterase activity were also tested. STZ treated animals performed poorly on MWM hence reflecting impairment of learning & memory. Further STZ treatment also produced a reduction in body weight, impairment of vascular endothelial function, decrease in serum nitrite / nitrate levels, along with increase in serum glucose, aortic & brain oxidative stress levels and brain acetylcholinesterase activity. Treatment of HMAP, Pitavastatin and Donepezil significantly reversed diabetes induced learning and memory, endothelial dysfunction, and changes in various biochemical levels. It may be concluded that STZ induces vascular dementia. 4'hydroxy-3'-methoxy acetophenone and Pitavastatin may be considered as potential pharmacological agents for the management of diabetes induced vascular dementia.
ESTHER : Sharma_2010_Curr.Neurovasc.Res_7_180
PubMedSearch : Sharma_2010_Curr.Neurovasc.Res_7_180
PubMedID: 20560881

Title : Memory restorative role of statins in experimental dementia: an evidence of their cholesterol dependent and independent actions - Dalla_2010_Pharmacol.Rep_62_784
Author(s) : Dalla Y , Singh N , Jaggi AS , Singh D
Ref : Pharmacol Rep , 62 :784 , 2010
Abstract : The study was aimed at investigating the effects of pitavastatin, simvastatin (lipophilic statins) and fluvastatin (hydrophilic statin) on memory deficits associated with Alzheimer's type dementia in mice. Dementia was induced with chronic administration of a high fat diet (HFD) or intracebroventricular streptozotocin (icv STZ, two doses of 3 mg/kg) in separate groups of animals. Memory of the animals was assessed by the Morris water maze (MWM) test. Brain thiobarbituric acid reactive species (TBARS) and reduced glutathione (GSH) levels were measured to assess total oxidative stress. Brain acetylcholinesterase (AChE) activity and total serum cholesterol levels were also measured. Icv STZ or HFD produced a significant impairment of learning and memory. Higher levels of brain AChE activity and TBARS and lower levels of GSH were observed in icv STZ- as well as HFD-treated animals. HFD-treated mice also showed a significant increase in total serum cholesterol levels. Pitavastatin and simvastatin each significantly attenuated STZ-induced memory deficits and biochemical changes; however, fluvastatin produced no significant effect on icv STZ-induced dementia or biochemical levels. Administration of any one of the three statins not only lowered HFD-induced rise in total serum cholesterol level but also attenuated HFD-induced memory deficits. Further pitavastatin and simvastatin administration also reversed HFD-induced changes in biochemicals level, while fluvastatin failed to produce any significant effect. This study demonstrates the potential of statins in memory dysfunctions associated with experimental dementia and provides evidence of their cholesterol-dependent and -independent actions.
ESTHER : Dalla_2010_Pharmacol.Rep_62_784
PubMedSearch : Dalla_2010_Pharmacol.Rep_62_784
PubMedID: 21098862

Title : Exploring mechanism of pioglitazone-induced memory restorative effect in experimental dementia - Kaur_2009_Fundam.Clin.Pharmacol_23_557
Author(s) : Kaur B , Singh N , Jaggi AS
Ref : Fundamental & Clinical Toxicology , 23 :557 , 2009
Abstract : The present study was undertaken to investigate possible mechanism of pioglitazone-induced beneficial effect in memory deficits associated with experimental dementia. Dementia was induced in Swiss albino mice by administration of streptozotocin (STZ; 3 mg/kg administered intracerebroventricularly on 1st & 3rd day). Morris Water-Maze test was employed to assess learning and memory of the animals. Brain acetylcholinesterase (AChE) activity was measured by Ell Mann's method. Brain thiobarbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels were measured by Ohokawa's and Beutler's method respectively to assess total oxidative stress. Blood glucose level was also measured. Streptozotocin (STZ) produced a significant decrease in water-maze performance of mice hence reflecting loss of learning and memory. Pioglitazone (20 mg/kg p.o. daily for 14 days) successfully attenuated STZ-induced memory deficits, without any significant per se effect on blood glucose levels. Higher levels of brain AChE activity, TBARS and lower levels of GSH were observed in STZ treated animals, which were significantly attenuated by pioglitazone. Further, the noted beneficial effect of pioglitazone on STZ-induced dementia was significantly abolished by pre-treatment of nitric oxide (NO) synthase inhibitor L-NAME (3 mg/kg i.p.) manifested in the terms of decrease in water-maze performance and increase in brain AChE activity as well as oxidative stress. It is concluded that anti-dementic effect of pioglitazone may involve central cholinergic, oxidative and NO pathways.
ESTHER : Kaur_2009_Fundam.Clin.Pharmacol_23_557
PubMedSearch : Kaur_2009_Fundam.Clin.Pharmacol_23_557
PubMedID: 19656209

Title : Modulation of celecoxib- and streptozotocin-induced experimental dementia of Alzheimer's disease by pitavastatin and donepezil - Sharma_2008_J.Psychopharmacol_22_162
Author(s) : Sharma B , Singh N , Singh M
Ref : J Psychopharmacol , 22 :162 , 2008
Abstract : Present study was designed to investigate modulation of experimental dementia by Pitavastatin and donepezil. Learning and memory of the swiss albino mice were studied on Morris water-maze. Celecoxib orally (p.o.)/Streptozotocin (STZ) intracerebroventricular administrations were used to induce experimental dementia. Brain acetyl cholinesterase activity was measured by EllMann's method to assess cholinergic activity of the brain. Brain thio barbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels were measured by Ohokawa's and Beutler's method respectively, to assess total oxidative stress in brain. Total serum cholesterol level was measured by Allain's method. Celecoxib/STZ treatments produced a significant loss of learning and memory. Pitavastatin/Donepezil successfully attenuated this Celecoxib/STZ induced dementia. Higher levels of brain acetyl-cholinesterase (AChE) activity, TBARS and lower level of GSH were observed in Celecoxib/STZ treated animals, which were significantly attenuated by Donepezil. Pitavastatin also attenuated the Celecoxib/STZ induced high levels of TBARS & low levels of GSH without effecting AChE activity and total serum cholesterol levels. Celecoxib induced dementia noted in the present study may be attributed to its stimulatory effect on amyloid beta-42, brain AChE activity, and oxidative stress. Sub-diabetogenic STZ induced memory deficits closely related to Alzheimer's disease. Reversal of Celecoxib/STZ induced memory deficits by Pitavastatin may be due to its antioxidative, anti beta amyloid aggregatory property, and by Donepezil, due to its anticholinesterase and neuroprotective actions.
ESTHER : Sharma_2008_J.Psychopharmacol_22_162
PubMedSearch : Sharma_2008_J.Psychopharmacol_22_162
PubMedID: 18208924

Title : Exploitation of HIV protease inhibitor Indinavir as a memory restorative agent in experimental dementia - Sharma_2008_Pharmacol.Biochem.Behav_89_535
Author(s) : Sharma B , Singh N , Singh M , Jaggi AS
Ref : Pharmacol Biochem Behav , 89 :535 , 2008
Abstract : The present study was undertaken to investigate the beneficial effect of HIV protease inhibitor Indinavir on memory deficits associated with experimental dementia of Alzheimer disease's (AD) type. Dementia was induced in Swiss albino mice by administration of Celecoxib (100 mg kg(-1) orally, daily for 9 days) or Streptozotocin (3 mg kg(-1) administered intracerebroventricularly on 1st and 3rd day) and the cognitive behaviors of Swiss albino mice were assessed using Morris water maze test. Brain acetyl cholinesterase (AChE) activity was measured by Ell Mann's method. Brain thiobarbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels were measured by Ohokawa's and Beutler's method respectively to assess total oxidative stress. Donepezil (0.1 mg kg(-1) i.p.) served as positive control in the present investigation. Celecoxib as well as Streptozotocin (STZ) produced a significant loss of learning and memory. Indinavir (100 and 200 mg kg(-1) orally) successfully attenuated Celecoxib as well as STZ induced cognitive deficits. Higher levels of brain AChE activity, TBARS and lower levels of GSH were observed in Celecoxib as well as STZ treated animals, which were significantly attenuated by Donepezil and Indinavir. Study highlights the potential of Indinavir in memory dysfunctions associated with dementia of AD.
ESTHER : Sharma_2008_Pharmacol.Biochem.Behav_89_535
PubMedSearch : Sharma_2008_Pharmacol.Biochem.Behav_89_535
PubMedID: 18343489

Title : Ameliorative role of Atorvastatin and Pitavastatin in L-Methionine induced vascular dementia in rats - Koladiya_2008_BMC.Pharmacol_8_14
Author(s) : Koladiya RU , Jaggi AS , Singh N , Sharma BK
Ref : BMC Pharmacol , 8 :14 , 2008
Abstract : BACKGROUND: Statins, HMG-CoA reductase inhibitors, are widely prescribed drugs for dyslipidemias. Recent studies have indicated number of cholesterol independent actions of statins including their beneficial effects on vascular endothelial dysfunction and memory deficits associated with dementia of Alzheimer's type. However the potential of statins in dementia of vascular origin still remains to be explored. Therefore, the present study has been designed to investigate the effect of Atorvastatin & Pitavastatin on vascular endothelial dysfunction associated memory deficits in rats. In this study L-Methionine induced vascular dementia was assessed by Morris water-maze (MWM) test. Biochemical analysis was also performed to unfold possible mechanism of statins mediated modulation of vascular dementia.
RESULTS: L-Methionine produced endothelial dysfunction as reflected by significant decrease in serum nitrite concentration. L-Methionine treated rats performed poorly on MWM indicating impairment of memory as well. These rats also showed a significant rise in brain oxidative stress, acetylcholinesterase (AChE) activity and serum total cholesterol levels. Both Atorvastatin as well as Pitavastatin attenuated L-Methionine induced endothelial dysfunction associated memory deficits. Statins also reversed L-Methionine induced rise in brain oxidative stress, AChE activity and serum cholesterol. CONCLUSION: The beneficial effects of statins may be attributed to their multiple effects and the study highlights the potential of these drugs in vascular dementia.
ESTHER : Koladiya_2008_BMC.Pharmacol_8_14
PubMedSearch : Koladiya_2008_BMC.Pharmacol_8_14
PubMedID: 18691432

Title : Palmitoyl-protein thioesterase 1 deficiency in Drosophila melanogaster causes accumulation of abnormal storage material and reduced life span - Hickey_2006_Genetics_172_2379
Author(s) : Hickey AJ , Chotkowski HL , Singh N , Ault JG , Korey CA , MacDonald ME , Glaser RL
Ref : Genetics , 172 :2379 , 2006
Abstract : Human neuronal ceroid lipofuscinoses (NCLs) are a group of genetic neurodegenerative diseases characterized by progressive death of neurons in the central nervous system (CNS) and accumulation of abnormal lysosomal storage material. Infantile NCL (INCL), the most severe form of NCL, is caused by mutations in the Ppt1 gene, which encodes the lysosomal enzyme palmitoyl-protein thioesterase 1 (Ppt1). We generated mutations in the Ppt1 ortholog of Drosophila melanogaster to characterize phenotypes caused by Ppt1 deficiency in flies. Ppt1-deficient flies accumulate abnormal autofluorescent storage material predominantly in the adult CNS and have a life span 30% shorter than wild type, phenotypes that generally recapitulate disease-associated phenotypes common to all forms of NCL. In contrast, some phenotypes of Ppt1-deficient flies differed from those observed in human INCL. Storage material in flies appeared as highly laminar spherical deposits in cells of the brain and as curvilinear profiles in cells of the thoracic ganglion. This contrasts with the granular deposits characteristic of human INCL. In addition, the reduced life span of Ppt1-deficient flies is not caused by progressive death of CNS neurons. No changes in brain morphology or increases in apoptotic cell death of CNS neurons were detected in Ppt1-deficient flies, even at advanced ages. Thus, Ppt1-deficient flies accumulate abnormal storage material and have a shortened life span without evidence of concomitant neurodegeneration.
ESTHER : Hickey_2006_Genetics_172_2379
PubMedSearch : Hickey_2006_Genetics_172_2379
PubMedID: 16452138
Gene_locus related to this paper: drome-CG12108

Title : Sildenafil improves acquisition and retention of memory in mice - Singh_2003_Indian.J.Physiol.Pharmacol_47_318
Author(s) : Singh N , Parle M
Ref : Indian Journal de Physiologie Pharmacol , 47 :318 , 2003
Abstract : Sildenafil (Viagra) has been introduced recently in market to correct male impotency and has gained immense popularity for its dramatic effects all over the world. The present study was designed to investigate the effect of sildenafil on learning and memory in mice using elevated plus maze. A total of XV groups of animals were employed in the present study. Central cholinergic pathways play a crucial role in learning and memory processes. Physostigmine, an anticholinesterase agent (0.5 mg, 1.0 mg kg(-1), i.p) was employed for its memory enhancing property and alprazolam a benzodiazepine receptor agonist served as a memory-impairing agent. In the present study, alprazolam produced anterograde amnesia (at 0.5 mg kg(-1), i.p) and retrograde amnesia (at 0.25 mg, 0.5 mg, 0.75 mg kg(-1), i.p.) in separate groups of animals. Caffeine at 5 mg, 10 mg and 20 mg kg(-1), i.p. (an established psychostimulant) did not show any significant change in learning and memory of mice. Sildenafil (at 8 mg kg(-1), i.p.) administered 30 minutes prior to training on first day produced a marginal decrease in transfer latency time on first day; whereas, sildenafil (at 2 mg, 4 mg, 8 mg kg(-1), i.p.) administered immediately after training on first day produced a dose-dependent improvement of memory in mice. However, further studies need to be carried out to elucidate the underlying mechanism of sildenafil as a memory enhancer.
ESTHER : Singh_2003_Indian.J.Physiol.Pharmacol_47_318
PubMedSearch : Singh_2003_Indian.J.Physiol.Pharmacol_47_318
PubMedID: 14723318

Title : Effects of BN-50730 (PAF receptor antagonist) and physostigmine (AChE inhibitor) on learning and memory in mice - Singh_1998_Methods.Find.Exp.Clin.Pharmacol_19_585
Author(s) : Singh N , Sharma A , Singh M
Ref : Methods Find Exp Clin Pharmacol , 19 :585 , 1998
Abstract : The present study was designed to investigate the effect of BN-50730, a PAF receptor antagonist, on learning and memory in mice using elevated plus-maze and to delineate the role of acetylcholine in modulating the effect of PAF receptor antagonist on learning and memory. BN-50730 administered immediately after plus-maze training on day 1 induced retrograde amnesia as indicated by a dose-dependent increase in transfer latency (TL) measured on day 2 whereas no such increase in TL was noted when BN-50730 (2.5 mg/kg, i.p.) was administered prior to plus-maze training. Physostigmine (0.5 mg/kg; 1.0 mg/kg, i.p.) administered 30 min prior to plus-maze training attenuated BN-50730-induced increase in TL measured on day 2. These results suggest that BN-50730, a PAF receptor antagonist, produced retrograde amnesia and physostigmine attenuated BN-50730-induced amnesia possibly through increased concentration of cerebral acetylcholine and a consequent increase in PAF release.
ESTHER : Singh_1998_Methods.Find.Exp.Clin.Pharmacol_19_585
PubMedSearch : Singh_1998_Methods.Find.Exp.Clin.Pharmacol_19_585
PubMedID: 9500121

Title : Endosulfan poisoning: a study of 22 cases - Singh_1992_J.Assoc.Physicians.India_40_87
Author(s) : Singh N , Singh CP , Kumar H , Brar GK
Ref : Journal of the Association of Physicians of India , 40 :87 , 1992
Abstract : Twenty two cases of endosulfan poisoning with their symptomatology are reported. The management and lack of awareness regarding specific treatment are highlighted.
ESTHER : Singh_1992_J.Assoc.Physicians.India_40_87
PubMedSearch : Singh_1992_J.Assoc.Physicians.India_40_87
PubMedID: 1629143