Castro NG

General

Full name : Castro Newton G

First name : Newton G

Mail : Departamento de Farmacologia Basica e Clinica, Instituto de Ciencias Biomedicas, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, RJ

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Country : Brazil

Email : ngcastro@farmaco.ufrj.br

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References (23)

Title : Design, Synthesis and Biological Evaluation of Novel Triazole N-acylhydrazone Hybrids for Alzheimer's Disease - de Freitas Silva_2020_Molecules_25_
Author(s) : de Freitas Silva M , Tardelli Lima E , Pruccoli L , Castro NG , Guimares MJR , F MRdS , Fonseca Nadur N , de Azevedo LL , Kummerle AE , Guedes IA , Dardenne LE , Gontijo VS , Tarozzi A , Viegas C
Ref : Molecules , 25 : , 2020
Abstract : Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that involves different pathogenic mechanisms. In this regard, the goal of this study was the design and synthesis of new compounds with multifunctional pharmacological activity by molecular hybridization of structural fragments of curcumin and resveratrol connected by an N-acyl-hydrazone function linked to a 1,4-disubstituted triazole system. Among these hybrid compounds, derivative 3e showed the ability to inhibit acetylcholinesterase activity, the intracellular formation of reactive oxygen species as well as the neurotoxicity elicited by Abeta(42) oligomers in neuronal SH-SY5Y cells. In parallel, compound 3e showed a good profile of safety and ADME parameters. Taken together, these results suggest that 3e could be considered a lead compound for the further development of AD therapeutics.
ESTHER : de Freitas Silva_2020_Molecules_25_
PubMedSearch : de Freitas Silva_2020_Molecules_25_
PubMedID: 32664425

Title : Design, synthesis and pharmacological evaluation of N-benzyl-piperidinyl-aryl-acylhydrazone derivatives as donepezil hybrids: Discovery of novel multi-target anti-alzheimer prototype drug candidates - Dias Viegas_2018_Eur.J.Med.Chem_147_48
Author(s) : Dias Viegas FP , de Freitas Silva M , Divino da Rocha M , Castelli MR , Riquiel MM , Machado RP , Vaz SM , Simoes de Lima LM , Mancini KC , Marques de Oliveira PC , Morais EP , Gontijo VS , da Silva FMR , D'Alincourt da Fonseca Pecanha D , Castro NG , Neves GA , Giusti-Paiva A , Vilela FC , Orlandi L , Camps I , Veloso MP , Leomil Coelho LF , Ionta M , Ferreira-Silva GA , Pereira RM , Dardenne LE , Guedes IA , de Oliveira Carneiro Junior W , Quaglio Bellozi PM , Pinheiro de Oliveira AC , Ferreira FF , Pruccoli L , Tarozzi A , Viegas C, Jr.
Ref : Eur Journal of Medicinal Chemistry , 147 :48 , 2018
Abstract : A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The molecular hybridization approach was based on the combination, in a single molecule, of the pharmacophoric N-benzyl-piperidine subunit of donepezil, the substituted hydroxy-piperidine fragment of the AChE inhibitor LASSBio-767, and an acylhydrazone linker, a privileged structure present in a number of synthetic aryl- and aryl-acylhydrazone derivatives with significant AChE and anti-inflammatory activities. Among them, compounds 4c, 4d, 4g and 4j presented the best AChE inhibitory activities, but only compounds 4c and 4g exhibited concurrent anti-inflammatory activity in vitro and in vivo, against amyloid beta oligomer (AbetaO) induced neuroinflammation. Compound 4c also showed the best in vitro and in vivo neuroprotective effects against AbetaO-induced neurodegeneration. In addition, compound 4c showed a similar binding mode to donepezil in both acetylated and free forms of AChE enzyme in molecular docking studies and did not show relevant toxic effects on in vitro and in vivo assays, with good predicted ADME parameters in silico. Overall, all these results highlighted compound 4c as a promising and innovative multi-target drug prototype candidate for AD treatment.
ESTHER : Dias Viegas_2018_Eur.J.Med.Chem_147_48
PubMedSearch : Dias Viegas_2018_Eur.J.Med.Chem_147_48
PubMedID: 29421570

Title : Design, synthesis and evaluation of novel feruloyl-donepezil hybrids as potential multitarget drugs for the treatment of Alzheimer's disease - Dias_2017_Eur.J.Med.Chem_130_440
Author(s) : Dias KS , de Paula CT , Dos Santos T , Souza IN , Boni MS , Guimaraes MJ , da Silva FM , Castro NG , Neves GA , Veloso CC , Coelho MM , de Melo IS , Giusti FC , Giusti-Paiva A , da Silva ML , Dardenne LE , Guedes IA , Pruccoli L , Morroni F , Tarozzi A , Viegas C, Jr.
Ref : Eur Journal of Medicinal Chemistry , 130 :440 , 2017
Abstract : A novel series of feruloyl-donepezil hybrid compounds were designed, synthesized and evaluated as multitarget drug candidates for the treatment of Alzheimer's Disease (AD). In vitro results revealed potent acetylcholinesterase (AChE) inhibitory activity for some of these compounds and all of them showed moderate antioxidant properties. Compounds 12a, 12b and 12c were the most potent AChE inhibitors, highlighting 12a with IC50 = 0.46 muM. In addition, these three most promising compounds exhibited significant in vivo anti-inflammatory activity in the mice paw edema, pleurisy and formalin-induced hyperalgesy models, in vitro metal chelator activity for Cu2+ and Fe2+, and neuroprotection of human neuronal cells against oxidative damage. Molecular docking studies corroborated the in vitro inhibitory mode of interaction of these active compounds on AChE. Based on these data, compound 12a was identified as a novel promising drug prototype candidate for the treatment of AD with innovative structural feature and multitarget effects.
ESTHER : Dias_2017_Eur.J.Med.Chem_130_440
PubMedSearch : Dias_2017_Eur.J.Med.Chem_130_440
PubMedID: 28282613

Title : Cardanol-derived AChE inhibitors: Towards the development of dual binding derivatives for Alzheimer's disease - Lemes_2015_Eur.J.Med.Chem_108_687
Author(s) : Lemes LF , de Andrade Ramos G , de Oliveira AS , da Silva FM , de Castro Couto G , da Silva Boni M , Guimaraes MJ , Souza IN , Bartolini M , Andrisano V , do Nascimento Nogueira PC , Silveira ER , Brand GD , Soukup O , Korabecny J , Romeiro NC , Castro NG , Bolognesi ML , Romeiro LA
Ref : Eur Journal of Medicinal Chemistry , 108 :687 , 2015
Abstract : Cardanol is a phenolic lipid component of cashew nut shell liquid (CNSL), obtained as the byproduct of cashew nut food processing. Being a waste product, it has attracted much attention as a precursor for the production of high-value chemicals, including drugs. On the basis of these findings and in connection with our previous studies on cardanol derivatives as acetylcholinesterase (AChE) inhibitors, we designed a novel series of analogues by including a protonable amino moiety belonging to different systems. Properly addressed docking studies suggested that the proposed structural modifications would allow the new molecules to interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, thus being able to act as dual binding inhibitors. To disclose whether the new molecules showed the desired profile, they were first tested for their cholinesterase inhibitory activity towards EeAChE and eqBuChE. Compound 26, bearing an N-ethyl-N-(2-methoxybenzyl)amine moiety, showed the highest inhibitory activity against EeAChE, with a promising IC50 of 6.6 muM, and a similar inhibition profile of the human isoform (IC50 = 5.7 muM). As another positive feature, most of the derivatives did not show appreciable toxicity against HT-29 cells, up to a concentration of 100 muM, which indicates drug-conform behavior. Also, compound 26 is capable of crossing the blood-brain barrier (BBB), as predicted by a PAMPA-BBB assay. Collectively, the data suggest that the approach to obtain potential anti-Alzheimer drugs from CNSL is worth of further pursuit and development.
ESTHER : Lemes_2015_Eur.J.Med.Chem_108_687
PubMedSearch : Lemes_2015_Eur.J.Med.Chem_108_687
PubMedID: 26735910

Title : Design, synthesis, and evaluation of guanylhydrazones as potential inhibitors or reactivators of acetylcholinesterase - Petronilho_2015_J.Enzyme.Inhib.Med.Chem__1
Author(s) : Petronilho EC , Renno MD , Castro NG , da Silva FM , Pinto AD , Figueroa-Villar JD
Ref : J Enzyme Inhib Med Chem , :1 , 2015
Abstract : Analogs of pralidoxime, which is a commercial antidote for intoxication from neurotoxic organophosphorus compounds, were designed, synthesized, characterized, and tested as potential inhibitors or reactivators of acetylcholinesterase (AChE) using the Ellman's test, nuclear magnetic resonance, and molecular modeling. These analogs include 1-methylpyridine-2-carboxaldehyde hydrazone, 1-methylpyridine-2-carboxaldehyde guanylhydrazone, and six other guanylhydrazones obtained from different benzaldehydes. The results indicate that all compounds are weak AChE reactivators but relatively good AChE inhibitors. The most effective AChE inhibitor discovered was the guanylhydrazone derived from 2,4-dinitrobenzaldehyde and was compared with tacrine, displaying similar activity to this reference material. These results indicate that guanylhydrazones as well as future similar derivatives may function as drugs for the treatment of Alzheimer's disease.
ESTHER : Petronilho_2015_J.Enzyme.Inhib.Med.Chem__1
PubMedSearch : Petronilho_2015_J.Enzyme.Inhib.Med.Chem__1
PubMedID: 26558640

Title : Astrocyte transforming growth factor beta 1 promotes inhibitory synapse formation via CaM kinase II signaling - Diniz_2014_Glia_62_1917
Author(s) : Diniz LP , Tortelli V , Garcia MN , Araujo AP , Melo HM , Seixas da Silva GS , De Felice FG , Alves-Leon SV , de Souza JM , Romao LF , Castro NG , Gomes FC
Ref : Glia , 62 :1917 , 2014
Abstract : The balance between excitatory and inhibitory synaptic inputs is critical for the control of brain function. Astrocytes play important role in the development and maintenance of neuronal circuitry. Whereas astrocytes-derived molecules involved in excitatory synapses are recognized, molecules and molecular mechanisms underlying astrocyte-induced inhibitory synapses remain unknown. Here, we identified transforming growth factor beta 1 (TGF-beta1), derived from human and murine astrocytes, as regulator of inhibitory synapse in vitro and in vivo. Conditioned media derived from human and murine astrocytes induce inhibitory synapse formation in cerebral cortex neurons, an event inhibited by pharmacologic and genetic manipulation of the TGF-beta pathway. TGF-beta1-induction of inhibitory synapse depends on glutamatergic activity and activation of CaM kinase II, which thus induces localization and cluster formation of the synaptic adhesion protein, Neuroligin 2, in inhibitory postsynaptic terminals. Additionally, intraventricular injection of TGF-beta1 enhanced inhibitory synapse number in the cerebral cortex. Our results identify TGF-beta1/CaMKII pathway as a novel molecular mechanism underlying astrocyte control of inhibitory synapse formation. We propose here that the balance between excitatory and inhibitory inputs might be provided by astrocyte signals, at least partly achieved via TGF-beta1 downstream pathways. Our work contributes to the understanding of the GABAergic synapse formation and may be of relevance to further the current knowledge on the mechanisms underlying the development of various neurological disorders, which commonly involve impairment of inhibitory synapse transmission. GLIA 2014;62:1917-1931.
ESTHER : Diniz_2014_Glia_62_1917
PubMedSearch : Diniz_2014_Glia_62_1917
PubMedID: 25042347

Title : LASSBio-881: an N-acylhydrazone transient receptor potential vanilloid subfamily type 1 antagonist orally effective against the hypernociception induced by capsaicin or partial sciatic ligation - Tributino_2010_Br.J.Pharmacol_159_1716
Author(s) : Tributino JL , Santos ML , Mesquita CM , Lima CK , Silva LL , Maia RC , Duarte CD , Barreiro EJ , Fraga CA , Castro NG , Miranda AL , Guimaraes MZ
Ref : British Journal of Pharmacology , 159 :1716 , 2010
Abstract : BACKGROUND AND PURPOSE: Compound LASSBio-881 is an orally effective antinociceptive that binds to cannabinoid receptors and is active mainly on the neurogenic component of pain models. We investigated whether transient receptor potential vanilloid subfamily type 1 (TRPV1) channels are involved in the effects of LASSBio-881. EXPERIMENTAL APPROACH: Modulation of capsaicin (CAP)- and low pH-induced currents was evaluated in TRPV1-expressing Xenopus oocytes. In vivo effects were evaluated in CAP-induced acute and inflammatory changes in nociception, as well as in partial sciatic ligation-induced thermal hypernociception. KEY
RESULTS: LASSBio-881 inhibited TRPV1 currents elicited by CAP with an IC(50) of 14 microM, and inhibited proton-gated currents by 70% at 20 microM. Functional interaction with CAP was surmountable. Locally applied LASSBio-881 decreased time spent in CAP-elicited nocifensive behaviour by 30%, and given orally it reduced measures of CAP- or carrageenan-evoked thermal hypernociception by 60 and 40% respectively. In addition, LASSBio-881 decreased the paw withdrawal responses to thermal stimuli of animals with sciatic neuropathy 7-11 days after nerve ligation, at a dose of 300 micromol*kg(-1)*day(-1) p.o. At this dose, hyperthermia was not observed within 4 h following oral administration. CONCLUSIONS AND IMPLICATIONS: LASSBio-881 is a TRPV1 antagonist that apparently competes with CAP. Accordingly, LASSBio- 881 inhibited nociception in models of acute, inflammatory and neuropathic pain presumed to involve TRPV1 signalling. These in vivo actions were not hindered by hyperthermia, a common side effect of other TRPV1 antagonists. We propose that the antinociceptive properties of LASSBio-881 are due to TRPV1 antagonism, although other molecular interactions may contribute to the effects of this multi-target drug candidate.
ESTHER : Tributino_2010_Br.J.Pharmacol_159_1716
PubMedSearch : Tributino_2010_Br.J.Pharmacol_159_1716
PubMedID: 20401963

Title : New potential AChE inhibitor candidates - de Paula_2009_Eur.J.Med.Chem_44_3754
Author(s) : de Paula AA , Martins JB , dos Santos ML , Nascente Lde C , Romeiro LA , Areas TF , Vieira KS , Gamboa NF , Castro NG , Gargano R
Ref : Eur Journal of Medicinal Chemistry , 44 :3754 , 2009
Abstract : We have theoretically studied new potential candidates of acetylcholinesterase (AChE) inhibitors designed from cardanol, a non-isoprenoid phenolic lipid of cashew Anacardium occidentale nut-shell liquid. The electronic structure calculations of fifteen molecule derivatives from cardanol were performed using B3LYP level with 6-31G, 6-31G(d), and 6-311+G(2d,p) basis functions. For this study we used the following groups: methyl, acetyl, N,N-dimethylcarbamoyl, N,N-dimethylamine, N,N-diethylamine, piperidine, pyrrolidine, and N,N-methylbenzylamine. Among the proposed compounds we identified that the structures with substitution by N,N-dimethycarbamoyl, N,N-dimethylamine, and pyrrolidine groups were better correlated to rivastigmine, and represent possible AChE inhibitors against Alzheimer disease.
ESTHER : de Paula_2009_Eur.J.Med.Chem_44_3754
PubMedSearch : de Paula_2009_Eur.J.Med.Chem_44_3754
PubMedID: 19446931

Title : Geissospermum vellosii stembark: anticholinesterase activity and improvement of scopolamine-induced memory deficits - Lima_2009_Pharmacol.Biochem.Behav_92_508
Author(s) : Lima JA , Costa RS , Epifanio RA , Castro NG , Rocha MS , Pinto AC
Ref : Pharmacol Biochem Behav , 92 :508 , 2009
Abstract : This study evaluated the cholinesterase inhibitory activity of an alkaloid-rich fraction of stembark from Geissospermum vellosii (PP), and its effect on memory tests in mice. PP inhibited rat brain and electric eel acetylcholinesterase, as well as horse serum butyrylcholinesterase in a concentration-dependent manner with mean IC(50) values of 39.3 microg/mL, 2.9 microg/mL, and 1.6 microg/mL, respectively. The main alkaloid with anticholinesterase activity in PP was isolated and identified as geissospermine. PP significantly reduced scopolamine-induced amnesia in the passive avoidance and Morris water maze tests, at 30 mg/kg i.p. (given 45 min before the test sessions). At the highest effective dose (60 mg/kg), administration of PP did not result in noticeable peripheral or central cholinergic side effects. Only after administration of 200 mg/kg, mice showed convulsions affecting the whole body followed by death. These results show that compounds present in G. vellosii stembark have anticholinesterase activity, and that they can revert cognitive deficits in a model of cholinergic hypofunction.
ESTHER : Lima_2009_Pharmacol.Biochem.Behav_92_508
PubMedSearch : Lima_2009_Pharmacol.Biochem.Behav_92_508
PubMedID: 19463267

Title : CNS-selective noncompetitive cholinesterase inhibitors derived from the natural piperidine alkaloid (-)-spectaline - Castro_2008_Eur.J.Pharmacol_580_339
Author(s) : Castro NG , Costa RS , Pimentel LS , Danuello A , Romeiro NC , Viegas C, Jr. , Barreiro EJ , Fraga CA , Bolzani VS , Rocha MS
Ref : European Journal of Pharmacology , 580 :339 , 2008
Abstract : LASSBio-767 [(-)-3-O-acetyl-spectaline] and LASSBio-822 [(-)-3-O-tert-Boc-spectaline] were recently described as cholinesterase inhibitors derived from the natural piperidine alkaloid (-)-spectaline, obtained from the flowers of Senna spectabilis (Fabaceae). We investigated their mechanism of inhibition of acetylcholinesterase and their efficacy in reversing scopolamine-induced amnesia. Competition assays with the substrate acetylthiocholine showed a concentration-dependent reduction in rat brain cholinesterase Vmax without changes in apparent Km. The kinetic data for LASSBio-767 and LASSBio-822 were best fit by a model of simple linear noncompetitive inhibition with Ki of 6.1 microM and 7.5 microM, respectively. A dilution assay showed a fast and complete reversal of inhibition, independent of incubation time. Simulated docking of the compounds into the catalytic gorge of Torpedo acetylcholinesterase showed interactions with the peripheral anionic site, but not with the catalytic triad. Anti-amnestic effects in mice were assessed in a step-down passive avoidance test and in the Morris water maze 30 min after injection of scopolamine (1 mg/kg i.p.). Saline, LASSBio-767, or LASSBio-822 was administered 15 min before scopolamine. Both compounds reversed the scopolamine-induced reduction in step-down latency at 0.1 mg/kg i.p. LASSBio-767 reversed scopolamine-induced changes in water maze escape latency at 1 mg/kg i.p. or p.o., while its cholinergic side effects were absent or mild up to 30 mg/kg i.p. (LD50 above 100 mg/kg i.p.). Thus, the (-)-spectaline derivatives are potent cholinergic agents in vivo, with a unique profile combining noncompetitive cholinesterase inhibition and CNS selectivity, with few peripheral side effects.
ESTHER : Castro_2008_Eur.J.Pharmacol_580_339
PubMedSearch : Castro_2008_Eur.J.Pharmacol_580_339
PubMedID: 18096154

Title : The magnitude of alpha7 nicotinic receptor currents in rat hippocampal neurons is dependent upon GABAergic activity and depolarization - Santos_2006_J.Pharmacol.Exp.Ther_319_376
Author(s) : Santos HR , Ribeiro HS , Setti-Perdigao P , Albuquerque EX , Castro NG
Ref : Journal of Pharmacology & Experimental Therapeutics , 319 :376 , 2006
Abstract : Hippocampal alpha7(*) nicotinic acetylcholine receptors modulate the release of GABA and glutamate. The control of functional receptor pools by cell firing or synaptic activity could therefore allow for a local adjustment of the sensitivity to cholinergic input upon changes in neuronal activity. We first investigated whether tonic depolarization or cell firing affected the function of alpha7(*). The amplitude of alpha7(*)-gated whole-cell currents in cultured rat hippocampal neurons exposed to high-extracellular K(+) (40 mM KCl) for 24 to 48 h increased 1.3 to 5.5 times. The proportion of alpha7(*)-responsive neurons (99%), the potency of acetylcholine, and the sensitivity to nicotinic antagonists were all unaffected. In contrast, block of spontaneous cell firing with tetrodotoxin for 24 h led to a 37% reduction in mean current amplitude. Reduced alpha7(*) responses were seen after a 24-h blockade of N-type calcium channels but not of L-type calcium channels, N-methyl-d-aspartate (NMDA), or non-NMDA receptor channels, protein kinase C, or calcium-calmodulin kinases II and IV. The N-type or L-type calcium channel antagonists omega-conotoxin GVIA and nifedipine did not prevent the current-potentiating effect of KCl. The GABA(A) antagonist picrotoxin led to a 44% reduction of the currents, despite increasing action potential firing, and also reversed the potentiating effect of KCl. Treatment with GABA, midazolam, or a GABA uptake blocker led to increased currents. These data indicate that alpha7(*)-gated currents in hippocampal neurons are regulated by GABAergic activity and suggest that depolarization-induced GABA release may underlie the effect of increased extracellular KCl.
ESTHER : Santos_2006_J.Pharmacol.Exp.Ther_319_376
PubMedSearch : Santos_2006_J.Pharmacol.Exp.Ther_319_376
PubMedID: 16837558

Title : New selective acetylcholinesterase inhibitors designed from natural piperidine alkaloids - Viegas_2005_Bioorg.Med.Chem_13_4184
Author(s) : Viegas C, Jr. , Bolzani VS , Pimentel LS , Castro NG , Cabral RF , Costa RS , Floyd C , Rocha MS , Young MC , Barreiro EJ , Fraga CA
Ref : Bioorganic & Medicinal Chemistry , 13 :4184 , 2005
Abstract : Five new piperidine alkaloids were designed from natural (-)-3-O-acetyl-spectaline and (-)-spectaline that were obtained from the flowers of Senna spectabilis (sin. Cassia spectabilis, Leguminosae). Two semi-synthetic analogues (7 and 9) inhibited rat brain acetylcholinesterase, showing IC50 of 7.32 and 15.1 microM, and were 21 and 9.5 times less potent against rat brain butyrylcholinesterase, respectively. Compound 9 (1mg/kg, i.p.) was fully efficacious in reverting scopolamine-induced amnesia in mice. The two active compounds (7 and 9) did not show overt toxic effects at the doses tested in vivo.
ESTHER : Viegas_2005_Bioorg.Med.Chem_13_4184
PubMedSearch : Viegas_2005_Bioorg.Med.Chem_13_4184
PubMedID: 15878668

Title : Binding of [3H]MK-801 in subcellular fractions of Schistosoma mansoni: evidence for interaction with nicotinic receptors - Pessoa_2005_Biochem.Pharmacol_69_1509
Author(s) : Pessoa RF , Castro NG , Noel F
Ref : Biochemical Pharmacology , 69 :1509 , 2005
Abstract : Several studies have suggested that l-glutamate is a putative neurotransmitter in Schistosoma mansoni. Recently, we detected the presence of low-affinity binding sites for [(3)H]kainic acid in the heterogeneous (P(1)) subcellular fraction of S. mansoni. In an attempt to characterize N-methyl-d-aspartate (NMDA) receptors in this worm, we performed binding assays with [(3)H]MK-801, a NMDA non-competitive antagonist, in the P(1) fraction of adult S. mansoni. In competition experiments, MK-801 (IC(50) approximately 200 microM) and ketamine (IC(50) approximately 500 microM) exhibited a low affinity for the sites labeled with [(3)H]MK-801. Along with the lack of modulation of this binding by glutamatergic agonists and antagonists and the absence of stereoselectivity for MK-801 isomers, these results suggest that [(3)H]MK-801 could label a site different from the classical NMDA receptor in S. mansoni. Based on the evidences that MK-801 interacts with mammalian muscle and central nervous system nicotinic receptors as a low-affinity noncompetitive antagonist, we have investigated the effects of MK-801 on the nicotine-induced flaccid paralysis of the worm, in vivo. The motility of S. mansoni was quantified by image analysis through a measure of displacement of the worm's extremities. In the presence of (-)-nicotine (10-100 microM), we observed an immediate paralysis of the worms, that was inhibited by 1mM MK-801. Besides nicotine, choline (10-50mM) was also able to inhibit the worm's motility. As a conclusion, we suggest that [(3)H]MK-801 binds to nicotinic receptors, and not NMDA receptors, in subcellular fractions of S. mansoni.
ESTHER : Pessoa_2005_Biochem.Pharmacol_69_1509
PubMedSearch : Pessoa_2005_Biochem.Pharmacol_69_1509
PubMedID: 15857615

Title : Spine density and dendritic branching pattern of hippocampal CA1 pyramidal neurons in neonatal rats chronically exposed to the organophosphate paraoxon - Santos_2004_Neurotoxicol_25_481
Author(s) : Santos HR , Cintra WM , Aracava Y , Maciel CM , Castro NG , Albuquerque EX
Ref : Neurotoxicology , 25 :481 , 2004
Abstract : The organophosphate cholinesterase (ChE) inhibitor paraoxon is the oxidized active metabolite of parathion, a pesticide whose use in agriculture has been matter of increasing concern. The present work was aimed at reproducing a prolonged exposure to low concentrations of paraoxon and assessing possible damage to the hippocampus during the period of most significant cholinergic development. Male Wistar rats were given, from P8 to P20, subcutaneous daily injections of paraoxon (0.1, 0.15 and 0.2mg/kg). The rate of body weight gain was reduced by all doses of paraoxon and brain ChE activity progressively decreased up to 60% by P21. Some deaths occurred in the beginning of the treatment, but the surviving animals showed neither convulsions nor overt signs of cholinergic hyperstimulation. Morphometric analysis of Lucifer Yellow-stained CA1 pyramidal neurons in coronal sections of the hippocampus showed that by P21 paraoxon caused a decrease in spine density on basal but not on secondary apical dendrites. The dendritic arborization and the pyramidal and granular cell body layers were not altered by paraoxon. ChE staining decreased in all hippocampal and dentate gyrus regions studied, whereas choline acetyltransferase (ChAT) and zinc-positive fibers remained as in control. In summary, chronic exposure to low paraoxon concentrations during the period of rapid brain development caused significant and selective decrease in basal dendritic spine density of the CA1 pyramidal neurons. Distinct modulation of the basal tree at the stratum oriens by the interplay of cholinergic afferent and GABAergic interneurons, as well as the remodeling process in response to a repetitive and rather mild paraoxon insult, may account for this selective susceptibility of basal dendritic spines. The hippocampal alterations described here occurred in the absence of toxic cholinergic signs and may affect brain development and cause functional deficits that could continue into adulthood.
ESTHER : Santos_2004_Neurotoxicol_25_481
PubMedSearch : Santos_2004_Neurotoxicol_25_481
PubMedID: 15019311

Title : Low concentrations of pyridostigmine prevent soman-induced inhibition of GABAergic transmission in the central nervous system: involvement of muscarinic receptors - Santos_2003_J.Pharmacol.Exp.Ther_304_254
Author(s) : Santos MD , Pereira EF , Aracava Y , Castro NG , Fawcett WP , Randall WR , Albuquerque EX
Ref : Journal of Pharmacology & Experimental Therapeutics , 304 :254 , 2003
Abstract : This study was designed to investigate the effects of the cholinesterase inhibitors soman and pyridostigmine bromide (PB) on synaptic transmission in the CA1 field of rat hippocampal slices. Soman (1-100 nM, 10-15 min) decreased the amplitude of GABAergic postsynaptic currents (IPSCs) evoked by stimulation of Schaffer collaterals and recorded from CA1 pyramidal neurons. It also decreased the amplitude and frequency of spontaneous IPSCs recorded from pyramidal neurons. Whereas the maximal effect of soman on evoked GABAergic transmission was observed at 10 nM, full cholinesterase inhibition was induced by 1 nM soman. After 10-15-min exposure of hippocampal slices to 100 nM PB, GABAergic transmission was facilitated and cholinesterase activity was not significantly affected. At nanomolar concentrations, soman and PB have no direct effect on GABA(A) receptors. The effects of soman and PB on GABAergic transmission were inhibited by the m2 receptor antagonist 11-[[[2-diethylamino-O-methyl]-1-piperidinyl] acetyl]-5,11-dihydrol-6H-pyridol[2,3-b][1,4]benzodiazepine-6- one (1 nM) and the m3 receptor antagonist 4-diphenylacetoxy-N-methyl-piperidine (100 nM), respectively, and by the nonselective muscarinic receptor antagonist atropine (1 microM). Thus, changes in GABAergic transmission are likely to result from direct interactions of soman and PB with m2 and m3 receptors, respectively, located on GABAergic fibers/neurons synapsing onto the neurons under study. Although the effects of 1 nM soman and 100 nM PB were diametrically opposed, they only canceled one another when PB was applied to the neurons before soman. Therefore, PB, acting via m3 receptors, can effectively counteract effects arising from the interactions of soman with m2 receptors in the brain.
ESTHER : Santos_2003_J.Pharmacol.Exp.Ther_304_254
PubMedSearch : Santos_2003_J.Pharmacol.Exp.Ther_304_254
PubMedID: 12490599

Title : Design, synthesis, and pharmacological profile of novel fused pyrazolo[4,3-d]pyridine and pyrazolo[3,4-b][1,8]naphthyridine isosteres: a new class of potent and selective acetylcholinesterase inhibitors - Barreiro_2003_J.Med.Chem_46_1144
Author(s) : Barreiro EJ , Camara CA , Verli H , Brazil-Mas L , Castro NG , Cintra WM , Aracava Y , Rodrigues CR , Fraga CA
Ref : Journal of Medicinal Chemistry , 46 :1144 , 2003
Abstract : A new family of tacrine (THA) analogues (7-9, 12), containing the azaheterocyclic pyrazolo[4,3-d]pyridine or pyrazolo[3,4-b][1,8]naphthyridine systems as isosteres of the quinoline ring of THA, has been synthesized. The compounds were tested in rat brain cholinesterases using Ellman's method, and all were fully efficacious in inhibiting the enzymes. Compounds 9 and 12b were the most potent against acetylcholinesterase (AChE), showing IC(50) of 6.0 and 6.4 microM, and were less active against rat brain butyrylcholinesterase, showing selectivity indexes of 5.3 and 20.9, respectively. Compounds 7-9 and 12 were also tested for their acute neurotoxicity in vitro, using cultured rat cortical cells. Compounds 7 and 8 were not significantly toxic; 9 was toxic at 500 microM, but not at 100 microM. The naphthyridine derivatives 12a and 12b showed a significant concentration-dependent neurotoxicity, being able to kill most cells at 500 microM. Molecular dynamic simulation using the X-ray crystal structure of AChE from Torpedo californica was used to explain the possible binding mode of these new THA isosteres.
ESTHER : Barreiro_2003_J.Med.Chem_46_1144
PubMedSearch : Barreiro_2003_J.Med.Chem_46_1144
PubMedID: 12646025

Title : A novel thienylhydrazone, (2-thienylidene)3,4-methylenedioxybenzoylhydrazine, increases inotropism and decreases fatigue of skeletal muscle - Gonzalez-Serratos_2001_J.Pharmacol.Exp.Ther_299_558
Author(s) : Gonzalez-Serratos H , Chang R , Pereira EF , Castro NG , Aracava Y , Melo PA , Lima PC , Fraga CA , Barreiro EJ , Albuquerque EX
Ref : Journal of Pharmacology & Experimental Therapeutics , 299 :558 , 2001
Abstract : This study was designed to investigate the effects on single skeletal muscle fibers of a novel thienylhydrazone, referred to as LASSBio-294, which is a bioisoster of pyridazinone compounds that inhibit the cyclic AMP-specific phosphodiesterase (PDE) 4. Twitch and fatigue were analyzed in single skeletal muscle fibers isolated from either the semitendinous or the tibialis anterior muscles dissected from the frog Rana pipiens. LASSBio-294 (12.5-100 microM) increased twitch tension, accelerated the maximal rate of tension decay during relaxation, and had very little effect in the maximal rate of tension development of muscle fibers directly stimulated at < or =30 Hz. The positive inotropic effect of LASSBio-294 developed slowly, reaching its maximum at 40 min and was inversely proportional to the frequency of stimulation, becoming negligible at 60 and 90 Hz. The concentration-response relationship for LASSBio-294-induced potentiation of twitch tension was bell-shaped, with maximal effect occurring at 25 microM. In addition, LASSBio-294 reduced development of fatigue induced by tetanic stimulation of the muscle fibers and reduced the time needed for 80% prefatigue tension recovery after fatigue had developed to 50% of the maximal pretetanic force. These effects of LASSBio-294 can be fully explained by stimulation of the sarcoplasmic reticulum Ca2+ pump and could be ascribed to an increase in cellular levels of cyclic AMP due to PDE inhibition. The novel thienylhydrazone LASSBio-294 may be useful for treatment of patients suffering from conditions in which muscle fatigue is a debilitating symptom (e.g., chronic heart failure).
ESTHER : Gonzalez-Serratos_2001_J.Pharmacol.Exp.Ther_299_558
PubMedSearch : Gonzalez-Serratos_2001_J.Pharmacol.Exp.Ther_299_558
PubMedID: 11602667

Title : Choline and acetylcholine have similar kinetic properties of activation and desensitization on the alpha7 nicotinic receptors in rat hippocampal neurons - Mike_2000_Brain.Res_882_155
Author(s) : Mike A , Castro NG , Albuquerque EX
Ref : Brain Research , 882 :155 , 2000
Abstract : The alpha7-type nicotinic acetylcholine receptor (nAChR) was recently found to be both fully activated and desensitized by choline, in addition to ACh. In order to understand the combined effects of the two agonists on alpha7 nAChR-mediated neuronal signaling, the kinetics of the receptor-channel's interaction with ACh and choline was examined. To this end, whole-cell and single-channel currents evoked by fast-switching pulses of the agonists were recorded in rat hippocampal neurons in culture. Currents evoked by equieffective concentrations of choline and ACh were very similar, except that choline-evoked currents decayed more quickly to the baseline after removal of the agonist, and that recovery from desensitization was faster with choline. The conductance of channels activated by choline and ACh was 91.5+/-8.5 and 82.9+/-11.6 pS, respectively. The mean apparent channel open times were close to 100 micros, with both agonists. After a 4-s exposure to concentrations up to 80 microM ACh or 600 microM choline, the extent of desensitization and the cumulative charge flow carried by the channels increased in the same proportion, until reaching a maximum. At higher concentrations of either agonist, the cumulative charge started decreasing with concentration, reflecting further desensitization. Kinetic modeling suggested that alpha7 nAChRs have at least two non-equivalent paths to desensitized states, and that choline dissociates faster than ACh from the receptor. Our results established that the main difference between choline and ACh is of affinity, and support the concept that the switching of endogenous agonist may change the desensitization-resensitization dynamics of alpha7 nAChRs.
ESTHER : Mike_2000_Brain.Res_882_155
PubMedSearch : Mike_2000_Brain.Res_882_155
PubMedID: 11056195

Title : Properties of neuronal nicotinic acetylcholine receptors: pharmacological characterization and modulation of synaptic function -
Author(s) : Albuquerque EX , Alkondon M , Pereira EF , Castro NG , Schrattenholz A , Barbosa CT , Bonfante-Cabarcas R , Aracava Y , Eisenberg HM , Maelicke A
Ref : Journal of Pharmacology & Experimental Therapeutics , 280 :1117 , 1997
PubMedID: 9067295

Title : Nicotinic receptor function in the mammalian central nervous system - Albuquerque_1995_Ann.N.Y.Acad.Sci_757_48
Author(s) : Albuquerque EX , Pereira EF , Castro NG , Alkondon M , Reinhardt S , Schroder H , Maelicke A
Ref : Annals of the New York Academy of Sciences , 757 :48 , 1995
Abstract : The diversity of neuronal nicotinic receptors (nAChRs) in addition to their possible involvement in such pathological conditions as Alzheimer's disease have directed our research towards the characterization of these receptors in various mammalian brain areas. Our studies have relied on electrophysiological, biochemical, and immunofluorescent techniques applied to cultured and acutely dissociated hippocampal neurons, and have been aimed at identifying the various subtypes of nAChRs expressed in the mammalian central nervous system (CNS), at defining the mechanisms by which CNS nAChR activity is modulated, and at determining the ion permeability of CNS nAChR channels. Our findings can be summarized as follows: (1) hippocampal neurons express at least three subtypes of CNS nAChRs--an alpha 7-subunit-bearing nAChR that subserves fast-inactivating, alpha-BGT-sensitive currents, which are referred to as type IA, and alpha 4 beta 2 nAChR that subserves slowly inactivating, dihydro-beta-erythroidine-sensitive currents, which are referred to as type II, and an alpha 3 beta 4 nAChR that subserves slowly inactivating, mecamylamine-sensitive currents, which are referred to as type III; (2) nicotinic agonists can activate a single type of nicotinic current in olfactory bulb neurons, that is, type IA currents; (3) alpha 7-subunit-bearing nAChR channels in the hippocampus have a brief lifetime, a high conductance, and a high Ca2+ permeability; (4) the peak amplitude of type IA currents tends to rundown with time, and this rundown can be prevented by the presence of ATP-regenerating compounds (particularly phosphocreatine) in the internal solution; (5) rectification of type IA currents is dependent on the presence of Mg2+ in the internal solution; and (6) there is an ACh-insensitive site on neuronal and nonneuronal nAChRs through which the receptor channel can be activated. These findings lay the groundwork for a better understanding of the physiological role of these receptors in synaptic transmission in the CNS.
ESTHER : Albuquerque_1995_Ann.N.Y.Acad.Sci_757_48
PubMedSearch : Albuquerque_1995_Ann.N.Y.Acad.Sci_757_48
PubMedID: 7611705

Title : alpha-Bungarotoxin-sensitive hippocampal nicotinic receptor channel has a high calcium permeability - Castro_1995_Biophys.J_68_516
Author(s) : Castro NG , Albuquerque EX
Ref : Biophysical Journal , 68 :516 , 1995
Abstract : The hippocampal nicotinic acetylcholine receptor (nAChR) is a newly identified ligand-gated ion channel that is blocked by the snake toxin alpha-bungarotoxin (alpha-BGT) and that probably contains the alpha 7 nAChR subunit in its structure. Here its ion selectivity was characterized and compared with that of the N-methyl-D-aspartate (NMDA) receptor channel. The reversal potentials (VR) of acetylcholine- and NMDA-activated whole-cell currents were determined under various ionic conditions. Using ion activities and a Goldman-Hodgkin-Katz equation for VR shifts in the presence of Ca2+, permeability ratios were calculated. For the alpha-BGT-sensitive nAChR, PNa/PCs was close to 1 and Cl- did not contribute to the currents. Changing the [Ca2+]0 from 1 to 10 mM, the VRs of the nAChR and NMDA currents were shifted by +5.6 +/- 0.4 and +8.3 +/- 0.4 mV, respectively, and the nAChR current decay was accelerated. These shifts yielded PCa/PCss of 6.1 +/- 0.5 for the nAChR channel and 10.3 +/- 0.7 for the NMDA channel. Thus, the neuronal alpha-BGT-sensitive nAChR is a cation channel considerably selective to Ca2+ and may mediate a fast rise in intracellular Ca2+ that would increase in magnitude with membrane hyperpolarization.
ESTHER : Castro_1995_Biophys.J_68_516
PubMedSearch : Castro_1995_Biophys.J_68_516
PubMedID: 7696505

Title : A novel agonist binding site on nicotinic acetylcholine receptors - Pereira_1993_J.Recept.Res_13_413
Author(s) : Pereira EF , Alkondon M , Tano T , Castro NG , Froes-Ferrao MM , Rozental R , Aronstam RS , Schrattenholz A , Maelicke A , Albuquerque EX
Ref : J Recept Res , 13 :413 , 1993
Abstract : This report provides evidence that physostigmine (Phy) and benzoquinonium (BZQ) are able to activate nicotinic acetylcholine receptors (nAChRs) through binding site(s) distinct from those of the natural transmitter, ACh. Such findings are in agreement with a second pathway of activation of nAChRs. Receptor activation may be modulated through the novel site, and, consequently, physiological processes involving nicotinic synapses could be controlled. Using patch clamp techniques, single channel currents activated by ACh and anatoxin were recorded from frog interosseal muscle fibers under cell-attached condition and outside-out patches excised from cultured rat hippocampal neurons. Whole cell nicotinic currents were also studied in the cultured neurons. In most of the neurons, nicotinic responses were blocked by the nicotinic antagonists methyllycaconitine (MLA) and alpha-bungarotoxin (alpha-BGT). Evaluation of the effects of Phy and BZQ on the muscle and on the alpha-BGT- and MLA-sensitive neuronal nAChRs demonstrated that both compounds were open channel blockers at these receptors. Furthermore, at low micromolar concentrations, Phy and BZQ activated the nAChRs of all preparations tested, such an effect being unexpectedly resistant to alpha-BGT or MLA. Thus, the nAChRs could be activated via two distinct binding sites: one for ACh and the other for Phy and BZQ. These findings and previous biochemical results led us to suggest that a putative endogenous ligand could bind to the new site and thereby regulate the activation of nAChRs in nicotinic synapses.
ESTHER : Pereira_1993_J.Recept.Res_13_413
PubMedSearch : Pereira_1993_J.Recept.Res_13_413
PubMedID: 8450498

Title : Brief-lifetime, fast-inactivating ion channels account for the alpha-bungarotoxin-sensitive nicotinic response in hippocampal neurons - Castro_1993_Neurosci.Lett_164_137
Author(s) : Castro NG , Albuquerque EX
Ref : Neuroscience Letters , 164 :137 , 1993
Abstract : Single-channel currents underlying the various types of nicotinic receptor-gated whole-cell currents (previously termed IA, IB, II and III) were identified in rat hippocampal neurons. In response to applied acetylcholine (ACh), most of the neurons showed a fast-decaying whole-cell current (type IA) that can be blocked by alpha-bungarotoxin (alpha-BGT). In these neurons, a novel nicotinic receptor channel was found, having a conductance of 73 pS and an open time of 0.12 ms at -80 mV. This channel showed a fast concentration-dependent inactivation that had a time constant of 0.5 ms at 1 mM ACh. A high Ca2+ permeability and the involvement of alpha 7 receptor subunits in the channel structure were suggested.
ESTHER : Castro_1993_Neurosci.Lett_164_137
PubMedSearch : Castro_1993_Neurosci.Lett_164_137
PubMedID: 7512242