Matsumoto K

References (34)

Title : Ursolic acid and its isomer oleanolic acid are responsible for the anti-dementia effects of Ocimum sanctum in olfactory bulbectomized mice - Nguyen_2022_J.Nat.Med__
Author(s) : Nguyen HT , Le XT , Van Nguyen T , Phung HN , Pham HTN , Nguyen KM , Matsumoto K
Ref : J Nat Med , : , 2022
Abstract : This study aims to clarify the bioactive constituents responsible for the anti-dementia effects of Ocimum sanctum Linn. ethanolic extract (OS) using olfactory bulbectomized (OBX) mice, an animal model of dementia. The effects of OS or its extract further fractionated with n-hexane (OS-H), ethyl acetate (OS-E), and n-butanol (OS-B) on the spatial cognitive deficits of OBX mice were elucidated by the modified Y-maze tests. The effects of the major constituents of the most active OS fraction were also elucidated using the reference drug donepezil. The administration of OS and OS-E ameliorated the spatial cognitive deficits caused by OBX, whereas OS-H or OS-B had no effect. Two major constituents, ursolic acid (URO) and oleanolic acid (OLE), and three minor constituents were isolated from OS-E. URO (6 and 12 mg/kg) and OLE (24 mg/kg) attenuated the OBX-induced cognitive deficits. URO (6 mg/kg) and donepezil reversed the OBX-induced down-regulation of vascular endothelial growth factor (VEGF) and choline acetyltransferase expression levels in the hippocampus. URO inhibited the ex vivo activity of acetylcholinesterase with similar efficacy to donepezil. URO inhibited the in vitro activity of acetylcholinesterase (IC(50) = 106.5 microM), while the effects of OS, OS-E, and other isolated compounds were negligible. These findings suggest that URO and OLE are responsible for the anti-dementia action of OS extract, whereas URO possesses a more potent anti-dementia effect than its isomer OLE. The effects of URO are, at least in part, mediated by normalizing the function of central cholinergic systems and VEGF protein expression.
ESTHER : Nguyen_2022_J.Nat.Med__
PubMedSearch : Nguyen_2022_J.Nat.Med__
PubMedID: 35218459

Title : Ocimum sanctum Linn. Extract Improves Cognitive Deficits in Olfactory Bulbectomized Mice via the Enhancement of Central Cholinergic Systems and VEGF Expression - Le_2021_Evid.Based.Complement.Alternat.Med_2021_6627648
Author(s) : Le XT , Nguyen HT , Nguyen TV , Pham HTN , Nguyen PT , Nguyen KM , Nguyen BV , Matsumoto K
Ref : Evid Based Complement Alternat Med , 2021 :6627648 , 2021
Abstract : This study aimed to clarify the antidementia effects of ethanolic extract of Ocimum sanctum Linn. (OS) and its underlying mechanisms using olfactory bulbectomized (OBX) mice. OBX mice were treated daily with OS or a reference drug, donepezil (DNP). Spatial and nonspatial working memory performance was measured using a modified Y maze test and a novel object recognition test, respectively. Brain tissues of the animals were subjected to histochemical and neurochemical analysis. OS treatment attenuated OBX-induced impairment of spatial and nonspatial working memories. OBX induced degeneration of septal cholinergic neurons, enlargement of the lateral ventricles, and suppression of hippocampal neurogenesis. OS and DNP treatment also depressed these histological damages. OS administration reduced ex vivo activity of acetylcholinesterase in the brain. OBX diminished the expression levels of genes coding vascular endothelial growth factor (VEGF) and VEGF receptor type 2 (VEGFR2). Treatment with OS and DNP reversed OBX-induced decrease in VEGF gene and protein expression levels without affecting the expression of the VEGFR2 gene. These results demonstrate that the administration of OS can lessen the cognitive deficits and neurohistological damages of OBX and that these actions are, at least in part, mediated by the enhancement of central cholinergic systems and VEGF expression.
ESTHER : Le_2021_Evid.Based.Complement.Alternat.Med_2021_6627648
PubMedSearch : Le_2021_Evid.Based.Complement.Alternat.Med_2021_6627648
PubMedID: 34306149

Title : Identification and Characterization of a New Carboxylesterase 2 Isozyme, mfCES2C, in the Small Intestine of Cynomolgus Monkeys - Ohura_2020_Drug.Metab.Dispos_48_146
Author(s) : Ohura K , Igawa Y , Tanaka M , Matsumoto K , Kasahara A , Wada N , Kubota K , Uno Y , Imai T
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 48 :146 , 2020
Abstract : In contrast to a single human carboxylesterase 2 (CES2) isozyme (hCE2), three CES2 genes have been identified in cynomolgus monkeys: mfCES2A, mfCES2B, and mfCES2C . Although mfCES2A protein is expressed in several organs, mfCES2B is a pseudogene and the phenotype of the mfCES2C gene has not yet been clarified in tissues. In previous studies, we detected an unidentified esterase in the region of CES2 mobility upon nondenaturing PAGE analysis of monkey intestinal microsomes, which showed immunoreactivity for anti-mfCES2A antibody. The aim of the present study was to identify this unidentified esterase from monkey small intestine. The esterase was separated on nondenaturing PAGE gel and digested in-gel with trypsin. The amino acid sequences of fragmented peptides were analyzed by tandem mass spectrometry. The unidentified esterase was shown to be identical to mfCES2C (XP_015298642.1, predicted from the genome sequence data). mfCES2C consists of 559 amino acid residues and shows approximately 90% homology with mfCES2A (561 amino acid residues). In contrast to the ubiquitous expression of mfCES2A, mfCES2C is only expressed in the small intestine, kidney, and skin. The hydrolytic properties of recombinant mfCES2C, expressed in HEK293 cells, with respect to p-nitrophenyl derivatives, 4-methylumbelliferyl acetate, and irinotecan were similar to those of recombinant mfCES2A. However, mfCES2C showed a hydrolase activity for O-n-valeryl propranolol higher than mfCES2A. It is concluded that the previously unidentified monkey intestinal CES2 is mfCES2C, which shows different hydrolytic properties to mfCES2A, depending on the substrate. SIGNIFICANCE STATEMENT: In the present research, we determined that mfCES2C, a novel monkey CES2 isozyme, is expressed in the small intestine and kidney of the cynomolgus monkey. Interestingly, mfCES2C showed a relatively wide substrate specificity for ester-containing compounds. These findings may, in early stages of drug development, support the use of in vitro-to-in vivo extrapolation for the intestinal hydrolysis of ester drugs in the cynomolgus monkey.
ESTHER : Ohura_2020_Drug.Metab.Dispos_48_146
PubMedSearch : Ohura_2020_Drug.Metab.Dispos_48_146
PubMedID: 31836607
Gene_locus related to this paper: macfa-a0a2k5uar1

Title : GPIHBP1 expression in gliomas promotes utilization of lipoprotein-derived nutrients - Hu_2019_Elife_8_e47178
Author(s) : Hu X , Matsumoto K , Jung RS , Weston TA , Heizer PJ , He C , Sandoval NP , Allan CM , Tu Y , Vinters HV , Liau LM , Ellison RM , Morales JE , Baufeld LJ , Bayley NA , He L , Betsholtz C , Beigneux AP , Nathanson DA , Gerhardt H , Young SG , Fong LG , Jiang H
Ref : Elife , 8 : , 2019
Abstract : GPIHBP1, a GPI-anchored protein of capillary endothelial cells, binds lipoprotein lipase (LPL) within the subendothelial spaces and shuttles it to the capillary lumen. GPIHBP1-bound LPL is essential for the margination of triglyceride-rich lipoproteins (TRLs) along capillaries, allowing the lipolytic processing of TRLs to proceed. In peripheral tissues, the intravascular processing of TRLs by the GPIHBP1-LPL complex is crucial for the generation of lipid nutrients for adjacent parenchymal cells. GPIHBP1 is absent from the capillaries of the brain, which uses glucose for fuel; however, GPIHBP1 is expressed in the capillaries of mouse and human gliomas. Importantly, the GPIHBP1 in glioma capillaries captures locally produced LPL. We use NanoSIMS imaging to show that TRLs marginate along glioma capillaries and that there is uptake of TRL-derived lipid nutrients by surrounding glioma cells. Thus, GPIHBP1 expression in gliomas facilitates TRL processing and provides a source of lipid nutrients for glioma cells.
ESTHER : Hu_2019_Elife_8_e47178
PubMedSearch : Hu_2019_Elife_8_e47178
PubMedID: 31169500

Title : Involvement of dopaminergic and cholinergic systems in social isolation-induced deficits in social affiliation and conditional fear memory in mice - Okada_2015_Neurosci_299_134
Author(s) : Okada R , Fujiwara H , Mizuki D , Araki R , Yabe T , Matsumoto K
Ref : Neuroscience , 299 :134 , 2015
Abstract : Post-weaning social isolation rearing (SI) in rodents elicits various behavioral abnormalities including attention deficit hyperactivity disorder-like behaviors. In order to obtain a better understanding of SI-induced behavioral abnormalities, we herein investigated the effects of SI on social affiliation and conditioned fear memory as well as the neuronal mechanism(s) underlying these effects. Four-week-old male mice were group-housed (GH) or socially isolated for 2-4weeks before the experiments. The social affiliation test and fear memory conditioning were conducted at the age of 6 and 7weeks, respectively. SI mice were systemically administered saline or test drugs 30min before the social affiliation test and fear memory conditioning. Contextual and auditory fear memories were elucidated 1 and 4days after fear conditioning. Social affiliation and contextual and auditory fear memories were weaker in SI mice than in GH mice. Methylphenidate (MPH), an inhibitor for dopamine transporters, ameliorated the SI-induced social affiliation deficit and the effect was attenuated by SCH23390, a D1 receptor antagonist, but not by sulpiride, a D2 receptor antagonist. On the other hand, tacrine, an acetylcholinesterase inhibitor, had no effect on this deficit. In contrast, tacrine improved SI-induced deficits in fear memories in a manner that was reversed by the muscarinic receptor antagonist scopolamine, while MPH had no effect on memory deficits. Neurochemical studies revealed that SI down-regulated the expression levels of the phosphorylated forms of neuro-signaling proteins, calmodulin-dependent kinase II (p-CaMKII), and cyclic AMP-responsive element binding protein (p-CREB), as well as early growth response protein-1 (Egr-1) in the hippocampus. The administration of MPH or tacrine before fear conditioning had no effect on the levels of the phosphorylated forms of the neuro-signaling proteins elucidated following completion of the auditory fear memory test; however, when analyzed 30min after the administration of the test drugs, tacrine significantly attenuated the SI-induced decrease in p-CaMKII, p-CREB, and Egr-1 in a manner reversible by scopolamine. Our results suggest that SI-induced deficits in social affiliation and conditioned fear memory were mediated by functional alterations to central dopaminergic and cholinergic systems, respectively.
ESTHER : Okada_2015_Neurosci_299_134
PubMedSearch : Okada_2015_Neurosci_299_134
PubMedID: 25943484

Title : Butea superba-Induced Amelioration of Cognitive and Emotional Deficits in Olfactory Bulbectomized Mice and Putative Mechanisms Underlying Its Actions - Mizuki_2014_J.Pharmacol.Sci_124_457
Author(s) : Mizuki D , Qi Z , Tanaka K , Fujiwara H , Ishikawa T , Higuchi Y , Matsumoto K
Ref : J Pharmacol Sci , 124 :457 , 2014
Abstract : This study investigated the effects of alcoholic extract of Butea superba (BS) on cognitive deficits and depression-related behavior using olfactory bulbectomized (OBX) mice and the underlying molecular mechanisms of its actions. OBX mice were treated daily with BS (100 and 300 mg/kg, p.o.) or reference drugs, tacrine (2.5 mg/kg, i.p.) and imipramine (10 mg/kg, i.p.) from day 3 after OBX. OBX impaired non-spatial and spatial cognitive performances, which were elucidated by the novel object recognition test and modified Y maze test, respectively. These deficits were attenuated by tacrine and BS but not imipramine. OBX animals exhibited depression-like behavior in the tail suspension test in a manner reversible by imipramine and BS but not tacrine. OBX down-regulated phosphorylation of synaptic plasticity-related signaling proteins: NMDA receptor, AMPA receptor, calmodulin-dependent kinase II, and cyclic AMP-responsive element-binding protein. OBX also reduced choline acetyltransferase in the hippocampus. BS and tacrine reversed these neurochemical alterations. Moreover, BS inhibited ex vivo activity of acetylcholinesterase in the brain. These results indicate that BS ameliorates not only cognition dysfunction via normalizing synaptic plasticity-related signaling and facilitating central cholinergic systems but also depression-like behavior via a mechanism differing from that implicated in BS amelioration of cognitive function in OBX animals.
ESTHER : Mizuki_2014_J.Pharmacol.Sci_124_457
PubMedSearch : Mizuki_2014_J.Pharmacol.Sci_124_457
PubMedID: 24646653

Title : Chemical profiling with HPLC-FTMS of exogenous and endogenous chemicals susceptible to the administration of chotosan in an animal model of type 2 diabetes-induced dementia - Niu_2014_J.Pharm.Biomed.Anal_104C_21
Author(s) : Niu Y , Li F , Inada C , Tanaka K , Watanabe S , Fujiwara H , Sasaki-Hamada S , Oka JI , Matsumoto K
Ref : J Pharm Biomed Anal , 104C :21 , 2014
Abstract : In our previous study, the daily administration of chotosan (CTS), a Kampo formula consisting of Uncaria and other 10 different crude drugs, ameliorated cognitive deficits in several animal models of dementia including type 2 diabetic db/db mice in a similar manner to tacrine, an acetylcholinesterase inhibitor. The present study investigated the metabonomics of CTS in db/db mice, a type 2 diabetes model, and m/m mice, a non-diabetes control strain, to identify the exogenous and endogenous chemicals susceptible to the administration of CTS using high performance liquid chromatography equipped with an orbitrap hybrid Fourier transform mass spectrometer. The results obtained revealed that the systemic administration of CTS for 20 days led to the distribution of Uncalia plant-derived alkaloids such as rhynchophylline, hirsuteine, and corynoxeine in the plasma and brains of db/db and m/m mice and induced alterations in four major metabolic pathways; i.e., (1) purine, (2) tryptophan, (3) cysteine and methionine, (4) glycerophospholipids in db/db mice. Moreover, glycerophosphocholine (GPC) levels in the plasma and brain were significantly higher in CTS-treated db/db mice than in vehicle-treated control animals. The results of the in vitro experiment using organotypic hippocampal slice cultures demonstrated that GPC (10-30muM), as well as tacrine, protected hippocampal cells from N-methyl-d-aspartate-induced excitotoxicity in a manner that was reversible with the muscarinic receptor antagonist scopolamine, whereas GPC had no effect on the activity of acetylcholinesterase in vitro. Our results demonstrated that some CTS constituents with neuropharmacological activity were distributed in the plasma and brain tissue following the systemic administration of CTS and may subsequently have affected some metabolic pathways including glycerophospholipid metabolism and cognitive function in db/db mice. Moreover, the present metabonomic analysis suggested that GPC is a putative endogenous chemical that may be involved in the tacrine-like actions of CTS in the present diabetic animal model.
ESTHER : Niu_2014_J.Pharm.Biomed.Anal_104C_21
PubMedSearch : Niu_2014_J.Pharm.Biomed.Anal_104C_21
PubMedID: 25459756

Title : Bacopa monnieri Ameliorates Memory Deficits in Olfactory Bulbectomized Mice: Possible Involvement of Glutamatergic and Cholinergic Systems - Le_2013_Neurochem.Res_38_2201
Author(s) : Le XT , Pham HT , Do PT , Fujiwara H , Tanaka K , Li F , Van Nguyen T , Nguyen KM , Matsumoto K
Ref : Neurochem Res , 38 :2201 , 2013
Abstract : This study investigated the effects of alcoholic extract of Bacopa monnieri (L.) Wettst. (BM) on cognitive deficits using olfactory bulbectomized (OBX) mice and the underlying molecular mechanisms of its action. OBX mice were treated daily with BM (50 mg/kg, p.o.) or a reference drug, tacrine (2.5 mg/kg, i.p.), 1 week before and continuously 3 days after OBX. Cognitive performance of the animals was analyzed by the novel object recognition test, modified Y maze test, and fear conditioning test. Brain tissues of OBX animals were used for neurochemical and immunohistochemical studies. OBX impaired non-spatial short-term memory, spatial working memory, and long-term fair memory. BM administration ameliorated these memory disturbances. The effect of BM on short-term memory deficits was abolished by a muscarinic receptor antagonist, scopolamine. OBX downregulated phosphorylation of synaptic plasticity-related signaling proteins: NR1 subunit of N-methyl-D-aspartate receptor, glutamate receptor 1 (GluR1), and calmodulin-dependent kinase II but not cyclic AMP-responsive element binding protein (CREB), and reduced brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus. OBX also reduced choline acetyltransferase in the hippocampus and cholinergic neurons in the medial septum, and enlarged the size of lateral ventricle. BM administration reversed these OBX-induced neurochemical and histological alterations, except the decrease of GluR1 phosphorylation, and enhanced CREB phosphorylation. Moreover, BM treatment inhibited ex vivo activity of acetylcholinesterase in the brain. These results indicate that BM treatment ameliorates OBX-induced cognition dysfunction via a mechanism involving enhancement of synaptic plasticity-related signaling and BDNF transcription and protection of cholinergic systems from OBX-induced neuronal damage.
ESTHER : Le_2013_Neurochem.Res_38_2201
PubMedSearch : Le_2013_Neurochem.Res_38_2201
PubMedID: 23949198

Title : Virtual screening against acetylcholine binding protein - Utsintong_2012_J.Biomol.Screen_17_204
Author(s) : Utsintong M , Rojsanga P , Ho KY , Talley TT , Olson AJ , Matsumoto K , Vajragupta O
Ref : J Biomol Screen , 17 :204 , 2012
Abstract : The nicotinic acetylcholine receptors (nAChRs) are a member of the ligand-gated ion channel family and play a key role in the transfer of information across neurological networks. The X-ray crystal structure of agonist-bound alpha(7) acetylcholine binding protein (AChBP) has been recognized as the most appropriate template to model the ligand-binding domain of nAChR for studying the molecular mechanism of the receptor-ligand interactions. Virtual screening of the National Cancer Institute diversity set, a library of 1990 compounds with nonredundant pharmacophore profiles, using AutoDock against AChBPs revealed 51 potential candidates. In vitro radioligand competition assays using [(3)H] epibatidine against the AChBPs from the freshwater snails, Lymnaea stagnalis, and from the marine species, Aplysia californica and the mutant (AcY55W), revealed seven compounds from the list of candidates that had micromolar to nanomolar affinities for the AChBPs. Further investigation on alpha(7)nAChR expressing in Xenopus oocytes and on the recombinant receptors with fluorescence resonance energy transfer (FRET)-based calcium sensor expressing in HEK cells showed that seven compounds were antagonists of alpha(7)nAChR, only one compound (NSC34352) demonstrated partial agonistic effect at low dose (10 microM), and two compounds (NSC36369 and NSC34352) were selective antagonists on alpha(7)nAchR with moderate potency. These hits serve as novel templates/scaffolds for development of more potent and specific in the AChR systems.
ESTHER : Utsintong_2012_J.Biomol.Screen_17_204
PubMedSearch : Utsintong_2012_J.Biomol.Screen_17_204
PubMedID: 21956172

Title : Synthesis of phenserine analogues and evaluation of their cholinesterase inhibitory activities - Shinada_2012_Bioorg.Med.Chem_20_4901
Author(s) : Shinada M , Narumi F , Osada Y , Matsumoto K , Yoshida T , Higuchi K , Kawasaki T , Tanaka H , Satoh M
Ref : Bioorganic & Medicinal Chemistry , 20 :4901 , 2012
Abstract : Phenserine is a potentially attractive drug for Alzheimer's disease. In order to further expand SAR study for inhibitions of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), the methyl group at the 3a-position of phenserine was replaced with an alkyl or alkenyl group, and its phenylcarbamoyl moiety was substituted at the o- or p-position. The synthetic methodology for these phenserine analogues includes the efficient cascade reactions for introduction of the 3a-substituent and assembly of the quaternary carbon center followed by reductive cyclization to the key pyrroloindoline structure. The bulkiness of the substituent at 3a-position of phenserine derivatives tends to reduce the inhibitory effect on AChE activity in the following order: methyl > ethyl > vinyl > propyl approximately allyl > reverse-prenyl groups. Among the series synthesized, the 3a-ethyl derivative demonstrated the highest AChE selectivity. In construct, the 3a-reverse-prenyl derivative indicated modest BuChE selectivity.
ESTHER : Shinada_2012_Bioorg.Med.Chem_20_4901
PubMedSearch : Shinada_2012_Bioorg.Med.Chem_20_4901
PubMedID: 22831800

Title : The effect of crebanine on memory and cognition impairment via the alpha-7 nicotinic acetylcholine receptor - Rojsanga_2012_Life.Sci_91_107
Author(s) : Rojsanga P , Boonyarat C , Utsintong M , Nemecz A , Yamauchi JG , Talley TT , Olson AJ , Matsumoto K , Vajragupta O
Ref : Life Sciences , 91 :107 , 2012
Abstract : AIMS: The aims of the present study were to investigate the effect of crebanine on memory and cognition impairment in mice and to elucidate the underlying molecular mechanisms. MAIN
METHODS: The memory-enhancing effects of crebanine were assessed with a water maze test using scopolamine-induced amnesic mice. The molecular mechanism was explored in silico by docking crebanine against acetylcholine binding proteins (AChBPs) and in vitro with a radioligand competition assay using (+/-)-[(3)H]-epibatidine. The pharmacological behavior was assessed by observing changes to the functional activity of alpha7-nAChRs expressed in Xenopus oocytes and by fluorescent assays on recombinant ligand gated ion channel (LGIC) receptors expressed in mammalian cells. KEY FINDINGS: The administration of crebanine significantly improved the cognitive deficits induced by scopolamine, as measured by the water maze test. The docking results demonstrated that crebanine bound to the active binding site of the AChBP template with a good docking energy. Crebanine significantly inhibited the binding of (+/-)-[(3)H]-epibatidine to AChBPs with K(i) values of 179 nM and 538 nM for Ls and Ac, respectively. Further functional assays performed using two separate protocols indicated that crebanine is an antagonist of the alpha7-nAChR with an IC(50) of 19.1muM. SIGNIFICANCE: The observed actions of crebanine against amnesia and its effect on alpha7-nAChRs will be beneficial for target-based drug design; crebanine or its scaffold can be used as the starting point to develop a drug for Alzheimer's disease. The cognition-enhancing effects of crebanine and the underlying mechanism based on alpha7-nAChRs are consistent with its traditional use. These findings demonstrate the potential utility of crebanine in the development of neurodegenerative therapy.
ESTHER : Rojsanga_2012_Life.Sci_91_107
PubMedSearch : Rojsanga_2012_Life.Sci_91_107
PubMedID: 22749860

Title : Reduced acetylcholinesterase activity in the fusiform gyrus in adults with autism spectrum disorders - Suzuki_2011_Arch.Gen.Psychiatry_68_306
Author(s) : Suzuki K , Sugihara G , Ouchi Y , Nakamura K , Tsujii M , Futatsubashi M , Iwata Y , Tsuchiya KJ , Matsumoto K , Takebayashi K , Wakuda T , Yoshihara Y , Suda S , Kikuchi M , Takei N , Sugiyama T , Irie T , Mori N
Ref : Arch Gen Psychiatry , 68 :306 , 2011
Abstract : CONTEXT: Both neuropsychological and functional magnetic resonance imaging studies have shown deficiencies in face perception in subjects with autism spectrum disorders (ASD). The fusiform gyrus has been regarded as the key structure in face perception. The cholinergic system is known to regulate the function of the visual pathway, including the fusiform gyrus. OBJECTIVES: To determine whether central acetylcholinesterase activity, a marker for the cholinergic system, is altered in ASD and whether the alteration in acetylcholinesterase activity, if any, is correlated with their social functioning. DESIGN: Using positron emission tomography and a radiotracer, N-[(11)C]methyl-4-piperidyl acetate ([(11)C]MP4A), regional cerebrocortical acetylcholinesterase activities were estimated by reference tissue-based linear least-squares analysis and expressed in terms of the rate constant k(3). Current and childhood autism symptoms in the adult subjects with ASD were assessed by the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview-Revised, respectively. Voxel-based analyses as well as region of interest-based methods were used for between-subject analysis and within-subject correlation analysis with respect to clinical variables. SETTING: Participants recruited from the community. PARTICIPANTS: Twenty adult subjects with ASD (14 male and 6 female; age range, 18-33 years; mean [SD] intelligence quotient, 91.6 [4.3]) and 20 age-, sex-, and intelligence quotient-matched healthy controls. RESULTS: Both voxel- and region of interest-based analyses revealed significantly lower [(11)C]MP4A k(3) values in the bilateral fusiform gyri of subjects with ASD than in those of controls (P < .05, corrected). The fusiform k(3) values in subjects with ASD were negatively correlated with their social disabilities as assessed by Autism Diagnostic Observation Schedule as well as Autism Diagnostic Interview-Revised. CONCLUSIONS: The results suggest that a deficit in cholinergic innervations of the fusiform gyrus, which can be observed in adults with ASD, may be related to not only current but also childhood impairment of social functioning.
ESTHER : Suzuki_2011_Arch.Gen.Psychiatry_68_306
PubMedSearch : Suzuki_2011_Arch.Gen.Psychiatry_68_306
PubMedID: 21383265

Title : Ameliorative effects of yokukansan on learning and memory deficits in olfactory bulbectomized mice - Yamada_2011_J.Ethnopharmacol_135_737
Author(s) : Yamada M , Hayashida M , Zhao Q , Shibahara N , Tanaka K , Miyata T , Matsumoto K
Ref : J Ethnopharmacol , 135 :737 , 2011
Abstract : AIM OF THE STUDY: Yokukansan (YKS) is a Japanese traditional herbal medicine and has been used for the treatment of the behavioral and psychological symptoms of dementia (BPSD). The present study aimed to clarify the effects of YKS on learning and memory impairments, and its mechanisms of action in olfactory bulbectomized (OBX) mice, one of the animal models of Alzheimer's disease (AD). MATERIALS AND METHODS: OBX or sham-operated ddY mice were treated with YKS or donepezil (DPZ), a reference drug, and their cognitive performances were tested by the modified Y-maze test, novel object recognition test, and fear conditioning test to elucidate the spatial working memory, non-spatial short-term memory, and long-term memory, respectively. After completing the behavioral experiments, the expression level of cholinergic marker proteins and the activity of acetylcholinesterase (AChE) in the brain were analyzed by western blotting and Ellman's method, respectively. RESULTS: OBX caused spatial working memory and non-spatial working memory impairments that were reversed by YKS and also by DPZ; however, YKS failed to affect the long-term memory deficits. Amelioration of the spatial working memory by YKS was reversible by scopolamine, a muscarinic receptor antagonist. YKS treatment reversed OBX-induced down-regulation of choline acetyltransferase and muscarinic muscarinic M(1) receptor expression without affecting muscarinic M(3) receptor expression or AChE activity. CONCLUSION: These results demonstrate that YKS improves short-term memory deficit caused by OBX and that the effect is at least partly mediated by muscarinic receptor stimulation and the normalization of central cholinergic systems. The present findings also suggest that YKS has a therapeutic effect not only on BPSD, but also on memory impairment of AD.
ESTHER : Yamada_2011_J.Ethnopharmacol_135_737
PubMedSearch : Yamada_2011_J.Ethnopharmacol_135_737
PubMedID: 21513784

Title : ASP4000, a slow-binding dipeptidyl peptidase 4 inhibitor, has antihyperglycemic activity of long duration in Zucker fatty rats - Tanaka-Amino_2010_Acta.Diabetol_47_43
Author(s) : Tanaka-Amino K , Matsumoto K , Hatakeyama Y , Takakura S , Mutoh S
Ref : Acta Diabetologia , 47 :43 , 2010
Abstract : ASP4000 ((2S)-1-{[(1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]hept-3-yl]carbonyl}-2-pyrrol idinecarbonitrile hydrochloride) is a novel, potent and selective dipeptidyl peptidase 4 (DPP IV, EC inhibitor (Keiko Tanaka-Amino et al. in Eur J pharmacol 59:444-449, 2008). The aim of the present study was to characterize the kinetic profile of and identify the long duration effect of the antihyperglycemic activity of ASP4000. ASP4000 was found to inhibit human recombinant DPP4 activity with a K(i) of 1.05 nM, a k(on) value of 22.3 x 10(5) M(-1) s(-1), and a k (off) of 2.35 x 10(-3) M(-1) s(-1), with higher affinity than that of vildagliptin. The kinetic studies indicate that both the formation and dissociation of ASP4000/DPP4 complex were faster than those of vildagliptin, and that ASP4000 slow-bindingly inhibits DPP4 with a different mode of inhibition than vildagliptin. In addition, ASP4000 augmented the insulin response and ameliorated the glucose excursion during the oral glucose tolerance test in Zucker fatty rats at 4 h post dosing. ASP4000 is expected to be a promising, long duration DPP4 inhibitor for type 2 diabetes.
ESTHER : Tanaka-Amino_2010_Acta.Diabetol_47_43
PubMedSearch : Tanaka-Amino_2010_Acta.Diabetol_47_43
PubMedID: 19238312

Title : ASP4,000, a novel, selective, dipeptidyl peptidase 4 inhibitor with antihyperglycemic activity - Tanaka-Amino_2008_Eur.J.Pharmacol_590_444
Author(s) : Tanaka-Amino K , Matsumoto K , Hatakeyama Y , Shima I , Takakura S , Muto S
Ref : European Journal of Pharmacology , 590 :444 , 2008
Abstract : ASP4,000, (2S)-1-{[(1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]hept-3-yl]carbonyl}-2-pyrroli dinecar bonitrile hydrochloride, is a novel dipeptidyl peptidase (DPP) 4 inhibitor. In the present study, we characterized the compound as an oral antidiabetic agent both in vitro and in vivo. ASP4,000 inhibited human recombinant DPP4 with an IC(50) value of 2.25 nM, and the enzyme-kinetic curve indicated that the inhibition type was competitive. In addition, ASP4,000 also potently inhibited DPP4 activity in human, rat, dog, and monkey plasma at concentrations of the order of 10(-9) M, and showed high selectivity against other related enzymes, including DPP8 and DPP9. The antihyperglycemic activity of ASP4,000 in vivo was examined using Zucker fa/fa rats, a type 2 diabetes animal model. A single oral administration of ASP4,000 at doses of 0.03-1 mg/kg suppressed plasma DPP4 activity, and then reduced the glucose level with increasing the active GLP-1 and insulin levels in oral glucose tolerance test. These results indicate that ASP4,000 is a potent, competitive, selective DPP4 inhibitor with antihyperglycemic activity, and could be a promising candidate agent for the treatment of patients with type 2 diabetes.
ESTHER : Tanaka-Amino_2008_Eur.J.Pharmacol_590_444
PubMedSearch : Tanaka-Amino_2008_Eur.J.Pharmacol_590_444
PubMedID: 18582861

Title : Choline biosensor constructed with chitinous membrane from soldier crab and its application in measuring cholinesterase inhibitory activities - Hsieh_2007_J.Pharm.Biomed.Anal_45_673
Author(s) : Hsieh BC , Matsumoto K , Cheng TJ , Yuu G , Chen RL
Ref : J Pharm Biomed Anal , 45 :673 , 2007
Abstract : An amperometric flow-injection choline biosensor was assembled utilizing natural chitinous membrane as the supporting material for biocatalyst immobilization, and the membrane was purified from Taiwanese soldier crab, Mictyris brevidactylus. The chitinous membrane (<50.0 microm in thickness) was covalently immobilized with choline oxidase (EC from Alcaligenes sp.) and then attached onto the platinum electrode of an amperometric flow cell. The flow cell served as the choline sensing device of the proposed FIA system. The sensor signal (peak height of the FIAgram) was linearly related to choline concentration (r=0.999 for choline up to 5.0mM) with low detection limit (S/N>3 for 10.0 microM choline) and high reproducibility (CV<3% for 1.0mM choline, n=7). The system was proved to be useful in measuring cholinesterase inhibitory activities of synthetic chemicals or natural products.
ESTHER : Hsieh_2007_J.Pharm.Biomed.Anal_45_673
PubMedSearch : Hsieh_2007_J.Pharm.Biomed.Anal_45_673
PubMedID: 17329059

Title : Hepatocyte growth factor promotes the number of PSD-95 clusters in young hippocampal neurons - Nakano_2007_Exp.Neurol_207_195
Author(s) : Nakano M , Takagi N , Takagi K , Funakoshi H , Matsumoto K , Nakamura T , Takeo S
Ref : Experimental Neurology , 207 :195 , 2007
Abstract : Hepatocyte growth factor (HGF) and its receptor are expressed in various regions of the brain and have protective effects against excitotoxic injuries. However, their effects on synapse formation remain to be elucidated. To determine whether HGF has the ability to alter synaptic function during development, we investigated changes in the number of synapse detected by double immunostaining for NMDA receptor subunits and a presynaptic marker in cultured young hippocampal neurons. Whereas application of HGF increased the number of cluster of synapsin, a presynaptic protein, the clusters of NMDA receptor subunits NR1 and NR2B were not altered. Interestingly, colocalization of PSD-95, a scaffolding protein of the receptor, with synapsin was increased by HGF treatment without a change in the total amount of it. In addition, we investigated the expression of surface NMDA receptor, neuroligin, and neurexin, which were assessed by use of a cell-surface biotinylation assay. The application of HGF did not change the surface expression of these proteins. Furthermore, we determined the release of glutamate in response to depolarization. Treatment with HGF promoted depolarization-evoked release of glutamate. These results suggest that HGF modulates the expression of the scaffolding protein of the NMDA receptor at the synapse and promotes maturation of excitatory synapses in young hippocampal neurons.
ESTHER : Nakano_2007_Exp.Neurol_207_195
PubMedSearch : Nakano_2007_Exp.Neurol_207_195
PubMedID: 17678646

Title : Chotosan, a kampo formula, ameliorates chronic cerebral hypoperfusion-induced deficits in object recognition behaviors and central cholinergic systems in mice - Zhao_2007_J.Pharmacol.Sci_103_360
Author(s) : Zhao Q , Murakami Y , Tohda M , Obi R , Shimada Y , Matsumoto K
Ref : J Pharmacol Sci , 103 :360 , 2007
Abstract : We previously demonstrated that the Kampo formula chotosan (CTS) ameliorated spatial cognitive impairment via central cholinergic systems in a chronic cerebral hypoperfusion (P2VO) mouse model. In this study, the object discrimination tasks were used to determine if the ameliorative effects of CTS on P2VO-induced cognitive deficits are a characteristic pharmacological profile of this formula, with the aim of clarifying the mechanisms by which CTS enhances central cholinergic function in P2VO mice. The cholinesterase inhibitor tacrine (THA) and Kampo formula saikokeishito (SKT) were used as controls. P2VO impaired object discrimination performance in the object recognition, location, and context tests. Daily administration of CTS (750 mg/kg, p.o.) and THA (2.5 mg/kg, i.p.) improved the object discrimination deficits, whereas SKT (750 mg/kg, p.o.) did not. In ex vivo assays, tacrine but not CTS or SKT inhibited cortical cholinesterase activity. P2VO reduced the mRNA expression of m(3) and m(5) muscarinic receptors and choline acetyltransferase but not that of other muscarinic receptor subtypes in the cerebral cortex. Daily administration of CTS and THA but not SKT reversed these expression changes. These results suggest that CTS and THA improve P2VO-induced cognitive impairment by normalizing the deficit of central cholinergic systems and that the beneficial effect on P2VO-induced cognitive deficits is a distinctive pharmacological characteristic of CTS.
ESTHER : Zhao_2007_J.Pharmacol.Sci_103_360
PubMedSearch : Zhao_2007_J.Pharmacol.Sci_103_360
PubMedID: 17409635

Title : Haplotypes and a novel defective allele of CES2 found in a Japanese population - Kim_2007_Drug.Metab.Dispos_35_1865
Author(s) : Kim SR , Sai K , Tanaka-Kagawa T , Jinno H , Ozawa S , Kaniwa N , Saito Y , Akasawa A , Matsumoto K , Saito H , Kamatani N , Shirao K , Yamamoto N , Yoshida T , Minami H , Ohtsu A , Saijo N , Sawada J
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 35 :1865 , 2007
Abstract : Human carboxylesterase 2 (hCE-2) is a member of the serine esterase superfamily and is responsible for hydrolysis of a wide variety of xenobiotic and endogenous esters. hCE-2 also activates an anticancer drug, irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin, CPT-11), into its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). In this study, a comprehensive haplotype analysis of the CES2 gene, which encodes hCE-2, in a Japanese population was conducted. Using 21 single nucleotide polymorphisms (SNPs), including 4 nonsynonymous SNPs, 100C>T (Arg(34)Trp, *2), 424G>A (Val(142)Met, *3), 1A>T (Met(1)Leu, *5), and 617G>A (Arg(206)His, *6), and a SNP at the splice acceptor site of intron 8 (IVS8-2A>G, *4), 20 haplotypes were identified in 262 Japanese subjects. In 176 Japanese cancer patients who received irinotecan, associations of CES2 haplotypes and changes in a pharmacokinetic parameter, (SN-38 + SN-38G)/CPT-11 area under the plasma concentration curve (AUC) ratio, were analyzed. No significant association was found among the major haplotypes of the *1 group lacking nonsynonymous or defective SNPs. However, patients with nonsynonymous SNPs, 100C>T (Arg(34)Trp) or 1A>T (Met(1)Leu), showed substantially reduced AUC ratios. In vitro functional characterization of the SNPs was conducted and showed that the 1A>T SNP affected translational but not transcriptional efficiency. These findings are useful for further pharmacogenetic studies on CES2-activated prodrugs.
ESTHER : Kim_2007_Drug.Metab.Dispos_35_1865
PubMedSearch : Kim_2007_Drug.Metab.Dispos_35_1865
PubMedID: 17640957
Gene_locus related to this paper: human-CES2

Title : Functional characterization of three naturally occurring single nucleotide polymorphisms in the CES2 gene encoding carboxylesterase 2 (HCE-2) - Kubo_2005_Drug.Metab.Dispos_33_1482
Author(s) : Kubo T , Kim SR , Sai K , Saito Y , Nakajima T , Matsumoto K , Saito H , Shirao K , Yamamoto N , Minami H , Ohtsu A , Yoshida T , Saijo N , Ohno Y , Ozawa S , Sawada J
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 33 :1482 , 2005
Abstract : Twelve single nucleotide polymorphisms (SNPs) in the human CES2 gene, which encodes a carboxylesterase, hCE-2 [human carboxylesterase 2 (EC], have been reported in the Japanese. In this report, we have examined functional alterations of three SNPs, a nonsynonymous SNP (100C>T, R34W), an SNP at the splice acceptor site in intron 8 (IVS8-2A>G), and one newly discovered nonsynonymous SNP (424G>A, V142M). For the two nonsynonymous SNPs, the corresponding variant cDNAs were expressed in COS-1 cells. Both the R34W and V142M variants showed little esterase activities toward the anticancer agent irinotecan and two typical carboxylesterase substrates, p-nitrophenol acetate and 4-methylumbelliferyl acetate, although increased levels of cDNA-mediated protein expression were observed by Western blotting as compared with the wild type. To investigate a possible splicing aberration in IVS8-2A>G, an in vitro splicing assay was utilized and transcripts derived from CES2 gene fragments of the wild type and IVS8-2A>G were compared. Sequence analysis of the cloned transcripts revealed that IVS8-2A>G yielded mostly aberrantly spliced transcripts, including a deleted exon or a 32-bp deletion proximal to the 5' end of exon 9, which resulted in truncated hCE-2 proteins. These results suggested that 100C>T (R34W), 424G>A (V142M), and IVS8-2A>G are functionally deficient SNPs.
ESTHER : Kubo_2005_Drug.Metab.Dispos_33_1482
PubMedSearch : Kubo_2005_Drug.Metab.Dispos_33_1482
PubMedID: 16033949

Title : Pnlip encoding pancreatic lipase is possible candidate for obesity QTL in the OLETF rat - Muramatsu_2005_Biochem.Biophys.Res.Commun_331_1270
Author(s) : Muramatsu Y , Yamada T , Taniguchi Y , Ogino T , Kose H , Matsumoto K , Sasaki Y
Ref : Biochemical & Biophysical Research Communications , 331 :1270 , 2005
Abstract : The Otsuka Long-Evans Tokushima Fatty (OLETF) rat exhibits polygenic obesity, and one of quantitative trait loci (QTLs) responsible for a susceptibility to obesity in the OLETF, Nidd6/of, has been mapped to the approximately 10-cM genomic region between D1Rat166 and D1Rat90 on chromosome 1 in (OLETF x normal) F2 intercross. In this study, we have attempted to identify the causal gene for the Nidd6/of QTL. A Nidd6/of congenic strain, constructed by introgressing the OLETF allele on the mapped Nidd6/of region in the normal F344 rat strain, confirmed the existence of the Nidd6/of as obesity QTL. The Nidd6/of region was refined to a approximately 2.3-cM genomic region between D1Rat225 and D1Rat90, using informative recombinants selected from (Nidd6/of congenic x F344) F1 x Nidd6/of congenic backcross progenies. Among 46 genes located within the approximately 2.3-cM region, pancreatic lipase gene, Pnlip, was regarded as the most prominent and physiologically relevant positional candidate for the Nidd6/of QTL. We found that Pnlip possesses an OLETF allele-specific increase of mRNA levels in the pancreas, and that the OLETF allele is longer in variable number of tandem repeat (VNTR) within the 5'-flanking region than normal alleles. We further showed that the Nidd6/of QTL completely cosegregates with Pnlip VNTR in the informative recombinants from (Nidd6/of congenic x F344) F1 x Nidd6/of congenic backcross progenies. These results suggest that Pnlip is possible candidate for the Nidd6/of QTL.
ESTHER : Muramatsu_2005_Biochem.Biophys.Res.Commun_331_1270
PubMedSearch : Muramatsu_2005_Biochem.Biophys.Res.Commun_331_1270
PubMedID: 15883013

Title : Does donepezil treatment slow the progression of hippocampal atrophy in patients with Alzheimer's disease? - Hashimoto_2005_Am.J.Psychiatry_162_676
Author(s) : Hashimoto M , Kazui H , Matsumoto K , Nakano Y , Yasuda M , Mori E
Ref : Am J Psychiatry , 162 :676 , 2005
Abstract : OBJECTIVE: The only approved pharmacological approach for the symptomatic treatment of Alzheimer's disease in Japan is the use of a cholinesterase inhibitor, donepezil hydrochloride. Recent in vivo and in vitro studies raise the possibility that cholinesterase inhibitors can slow the progression of Alzheimer's disease. The purpose of the present study was to determine whether donepezil has a neuroprotective effect in Alzheimer's disease by using the rate of hippocampal atrophy as a surrogate marker of disease progression. METHOD: In a prospective cohort study, 54 patients with Alzheimer's disease who received donepezil treatment and 93 control patients with Alzheimer's disease who never received anti-Alzheimer drugs underwent magnetic resonance imaging (MRI) twice at a 1-year interval. The annual rate of hippocampal atrophy of each subject was determined by using an MRI-based volumetric technique. Background characteristics, age, sex, disease duration, education, MRI interval, apolipoprotein E (APOE) genotype, and baseline Alzheimer's Disease Assessment Scale score were comparable between the treated and control groups.
RESULTS: The mean annual rate of hippocampal volume loss among the treated patients (mean=3.82%, SD=2.84%) was significantly smaller than that among the control patients (mean=5.04%, SD=2.54%). Upon analysis of covariance, where those confounding variables (age, sex, disease duration, education, MRI interval, APOE genotype, and baseline Alzheimer's Disease Assessment Scale score) were entered into the model as covariates, the effect of donepezil treatment on hippocampal atrophy remained significant.
CONCLUSIONS: Donepezil treatment slows the progression of hippocampal atrophy, suggesting a neuroprotective effect of donepezil in Alzheimer's disease.
ESTHER : Hashimoto_2005_Am.J.Psychiatry_162_676
PubMedSearch : Hashimoto_2005_Am.J.Psychiatry_162_676
PubMedID: 15800138

Title : Improvement of endothelial dysfunction by angiotensin II blockade accompanied by induction of vascular hepatocyte growth factor system in diabetic spontaneously hypertensive rats - Matsumoto_2003_Heart.Vessels_18_18
Author(s) : Matsumoto K , Morishita R , Tomita N , Moriguchi A , Komai N , Aoki M , Nakamura T , Higaki J , Ogihara T
Ref : Heart Vessels , 18 :18 , 2003
Abstract : Hepatocyte growth factor (HGF) is a unique growth factor with many protective functions. Previously, we demonstrated that HGF stimulated growth of endothelial cells without replication of vascular smooth muscle cells (VSMC) and that angiotensin (Ang) II significantly decreased local HGF production in VSMC. Moreover, we also reported that high glucose significantly decreased local vascular HGF production. Therefore, we examined effects of Ang II blockade on vascular HGF expression and endothelial injury in diabetic hypertensive rats. An angiotensin-converting enzyme inhibitor (quinapril) and an Ang II type 1 receptor antagonist (GA-0113) or vehicle was administrated to diabetic spontaneously hypertensive rats (SHR-DM), in whom diabetes was induced by streptozotocin. Endothelial function was evaluated by the vasodilator response to acetylcholine, and the expression of vascular HGF and its receptor, c-met, was examined by immunohistochemistry. Both quinapril and GA-0113 significantly improved the vasodilator response to acetylcholine ( P < 0.01), while vehicle did not as compared to untreated normotensive Wistar-Kyoto rats (WKY). We next examined the effects of Ang II blockade on vascular HGF expression in SHR-DM. Importantly, the vascular HGF level was markedly decreased in SHR-DM as compared to WKY, while Ang II blockade by quinapril or GA-0113 significantly increased positive staining for HGF in SHR-DM. Similarly, staining of its specific receptor, c-met, was less in the blood vessels of SHR-DM as compared to WKY. In contrast, Ang II blockade also significantly increased c-met production in SHR-DM. The present data demonstrated the improvement of endothelial dysfunction by Ang II blockade in SHR-SM, accompanied by an increase in vascular HGF and c-met.
ESTHER : Matsumoto_2003_Heart.Vessels_18_18
PubMedSearch : Matsumoto_2003_Heart.Vessels_18_18
PubMedID: 12644877

Title : Impaired endothelial dysfunction in diabetes mellitus rats was restored by oral administration of prostaglandin I2 analogue - Matsumoto_2002_J.Endocrinol_175_217
Author(s) : Matsumoto K , Morishita R , Tomita N , Moriguchi A , Yamasaki K , Aoki M , Nakamura T , Higaki J , Ogihara T
Ref : J Endocrinol , 175 :217 , 2002
Abstract : We have previously reported that a decrease in hepatocyte growth factor (HGF), which has many protective functions against endothelial damage by high d-glucose, might be a trigger of endothelial injury. However, the regulation of vascular HGF in diabetes mellitus (DM) has not been clarified in vivo, although vascular disease is frequently observed in DM patients. In addition, our previous report revealed that a prostaglandin I(2) (PGI(2)) analogue prevented endothelial cell death through the induction of vascular HGF production in cultured human epithelial cells. Thus, in this study, we examined the effects of a PGI(2) analogue in the regulation of the local HGF system using DM rats. A PGI(2) analogue (beraprost sodium; 300 and 600 micro g/kg per day) or vehicle was administered to 16-week-old DM rats induced by administration of streptozotocin for 28 days. Endothelial function was evaluated by the vasodilator response to acetylcholine, and the expression of vascular HGF mRNA was measured by Northern blotting. Of importance, expression of HGF mRNA was significantly decreased in the blood vessels of DM rats as compared with non-DM (P<0.01). In addition, the in vitro vasodilator response of the abdominal aorta to acetylcholine was markedly impaired in DM rats. Importantly, the vasodilator response was restored by PGI(2) treatment in a dose-dependent manner (P<0.01), whereas N(omega)-nitro-l-arginine methyl ester inhibited the restoration of endothelial function. Of particular interest, vascular HGF mRNA and protein were significantly increased in the blood vessels of DM rats treated with PGI(2) as compared with vehicle. Similarly, an increase in HGF protein was also confirmed by immunohistochemical analysis. In addition, the specific HGF receptor, c-met, was also increased by PGI(2) treatment. Overall, this study demonstrated that treatment with a PGI(2) analogue restored endothelial dysfunction in DM rats, accompanied by the induction of vascular HGF and c-met expression. Increased local vascular HGF production by a PGI(2) analogue may prevent endothelial injury, potentially resulting in the improvement of endothelial dysfunction.
ESTHER : Matsumoto_2002_J.Endocrinol_175_217
PubMedSearch : Matsumoto_2002_J.Endocrinol_175_217
PubMedID: 12379506

Title : Ameliorative effect of tacrine on spatial memory deficit in chronic two-vessel occluded rats is reversible and mediated by muscarinic M1 receptor stimulation - Murakami_2000_Behav.Brain.Res_109_83
Author(s) : Murakami Y , Ikenoya M , Matsumoto K , Li H , Watanabe H
Ref : Behavioural Brain Research , 109 :83 , 2000
Abstract : Our previous study demonstrated that permanent two-vessel occlusion (2VO)-induced working memory deficit was improved by daily administration of tacrine, a cholinesterase inhibitor. In this study, we investigated the mechanism underlying the effects of tacrine in 2VO rats using the eight-arm radial maze task. Daily administration of tacrine (0.1 or 0.3 mg/kg i.p.) started 5 weeks after the 2VO operation significantly improved the maze performance. In the delay-interposition task, a significant impairment of maze performance was observed in the tacrine (0.3 mg/kg, i.p.)-treated rats at a delay of 90 min but not delays of 5 or 30 min. Sham-operated rats were not affected by delay. After leaving animals with no further treatment for 4 weeks, the tacrine-pretreated 2VO rats showed significantly impaired performance compared to the sham-operated control animals. However, the performance of the tacrine-pretreated 2VO rats was significantly improved by restarting the daily administration of tacrine (0.3 mg/kg, i.p.). The effect of tacrine was reversed by the muscarinic antagonist scopolamine and the selective M1 antagonist pirenzepine. Moreover, a microdialysis study revealed that tacrine (1 or 3 mg/kg, i.p.) increased the extracellular acetylcholine (ACh) level for a period of over 3 h in the cerebral cortex of 2VO rats. These findings suggest that the ameliorative effect of tacrine on the spatial memory deficit in 2VO rats is reversible and may be mediated by stimulating the muscarinic M1 receptor via elevation of the extracellular ACh level in the brain.
ESTHER : Murakami_2000_Behav.Brain.Res_109_83
PubMedSearch : Murakami_2000_Behav.Brain.Res_109_83
PubMedID: 10699660

Title : In vivo transfer of human hepatocyte growth factor gene accelerates re-endothelialization and inhibits neointimal formation after balloon injury in rat model - Hayashi_2000_Gene.Ther_7_1664
Author(s) : Hayashi K , Nakamura S , Morishita R , Moriguchi A , Aoki M , Matsumoto K , Nakamura T , Kaneda Y , Sakai N , Ogihara T
Ref : Gene Therapy , 7 :1664 , 2000
Abstract : Although most therapeutic strategies to prevent restenosis are designed to inhibit vascular smooth muscle cell (VSMC) proliferation directly, VSMC proliferation might be indirectly inhibited by re-endothelialization, as endothelial cells secrete antiproliferative and antithrombotic substances. We hypothesized that application of an endothelium-specific growth factor to balloon-injured arteries could accelerate re-endothelialization, thereby attenuating intimal hyperplasia. In this study, we investigated in vivo gene transfer of human HGF that exclusively stimulated endothelial cells without replication of VSMC growth into injured vessels. Transfection of human HGF gene into rat balloon-injured carotid artery resulted in significant inhibition of neointimal formation up to at least 8 weeks after transfection, accompanied by detection of human immunoreactive HGF. Induction of re-endothelialization induced by overexpression of human HGF gene transfer into balloon-injured vessels is supported by several lines of evidence: (1) Administration of HGF vector. but not control vector, markedly inhibited neointimal formation, accompanied by a significant increase in vascular human and rat HGF concentrations. (2) Planimetric analysis demonstrated a significant increase in re-endothelialized area in arteries transfected with human HGF vector. (3) Induction of NO content in balloon-injured vessels transfected with human HGF vector was observed in accordance with the recovery of endothelial vasodilator properties in response to acetylcholine. As endogenous HGF expression in balloon-injured vessels was significantly decreased as compared with normal vessels, the present study demonstrated the successful inhibition of neointimal formation by transfection of human HGF gene as 'cytokine supplement therapy' in a rat balloon injury model.
ESTHER : Hayashi_2000_Gene.Ther_7_1664
PubMedSearch : Hayashi_2000_Gene.Ther_7_1664
PubMedID: 11083475

Title : Tacrine improves working memory deficit caused by permanent occlusion of bilateral common carotid arteries in rats - Murakami_1997_Jpn.J.Pharmacol_75_443
Author(s) : Murakami Y , Tanaka E , Sakai Y , Matsumoto K , Li HB , Watanabe H
Ref : Japanese Journal of Pharmacology , 75 :443 , 1997
Abstract : Effect of tacrine, a cholinesterase inhibitor, on spatial acquisition deficit caused by permanent occlusion of bilateral common carotid arteries (2VO) was examined by using the conventional 8-arm and the 4-arm baited radial maze tasks in rats. Daily administration of tacrine (0.1 and 0.3 mg/kg, i.p.) 1 month after 2VO operation significantly improved the impaired spatial acquisition in the conventional maze task. This treatment also ameliorated the 2VO-induced working but not reference memory deficit in the 4-arm baited radial maze task. These results suggest that tacrine improvement of working memory deficit in the 2VO rats is due to stimulation of central cholinergic systems.
ESTHER : Murakami_1997_Jpn.J.Pharmacol_75_443
PubMedSearch : Murakami_1997_Jpn.J.Pharmacol_75_443
PubMedID: 9469652

Title : Paeoniflorin attenuates learning impairment of aged rats in operant brightness discrimination task - Ohta_1994_Pharmacol.Biochem.Behav_49_213
Author(s) : Ohta H , Matsumoto K , Shimizu M , Watanabe H
Ref : Pharmacol Biochem Behav , 49 :213 , 1994
Abstract : The effects of paeoniflorin isolated from peony were examined on an aging-induced learning deficit in an operant brightness discrimination task in Fischer 344 rats. Learning in aged (25 months) rats was significantly impaired compared with young (5 months) rats. Daily administration of paeoniflorin (0.01 mg/kg, PO) significantly attenuated the learning impairment in aged rats, whereas it did not affect the learning in young rats. Although tacrine (0.3 and 1 mg/kg, IP), a cholinesterase inhibitor, also did not affect the learning in young rats, it slightly augmented the aging-induced learning deficit in the present task. These data indicate the therapeutic potential of paeoniflorin in the treatment of senile dementia and aging-induced cognitive dysfunction.
ESTHER : Ohta_1994_Pharmacol.Biochem.Behav_49_213
PubMedSearch : Ohta_1994_Pharmacol.Biochem.Behav_49_213
PubMedID: 7816876

Title : Carbachol-induced sodium current in guinea pig ventricular myocytes is not regulated by guanine nucleotides - Shirayama_1993_J.Pharmacol.Exp.Ther_265_641
Author(s) : Shirayama T , Matsumoto K , Pappano AJ
Ref : Journal of Pharmacology & Experimental Therapeutics , 265 :641 , 1993
Abstract : Muscarinic (M2) receptor occupancy by carbachol induces a tetrodotoxin- and pertussis toxin-resistant Na+ current which underlies its positive inotropic effect in guinea pig ventricular cells. We tested the effect of activating [GTP gamma S, Gpp(NH)p] and inactivating (GDP beta S) guanine nucleotides on this carbachol-induced current because guanine nucleotide binding proteins are reported to transduce the effect of muscarinic agonist. A whole-cell voltage clamp method was used. The carbachol (300 microM)-induced current was not significantly changed at any membrane voltage in the absence and the presence of 10 microM GTP gamma S, 100 microM Gpp(NH)p or 500 microM GDP beta S in the patch pipette (inward current amplitude at -80 mV: -21 +/- 1.5 pA, control; -22 +/- 1.3 pA, GTP gamma S; -20, -16 pA, Gpp(NH)p; -20 +/- 2.3 pA, GDP beta S; n = 31, 11, 2 and 14, respectively). The current amplitude was not affected by prolonged dialysis (120 min) of the cell with Gpp(NH)p and/or by the presence of greater concentrations of guanine nucleotides. On the other hand, 10 microM GTP gamma S directly activated the muscarinic K+ channel current within 60 sec after patch rupture in atrial myocytes; either GTP gamma S or GDP beta S (500 microM) occluded activation of this current by carbachol. When isoproterenol had increased L-type Ca++ current in ventricular myocytes, carbachol-induced inhibition of this current was suppressed when GTP gamma S (10 microM) was present in the pipette solution. Therefore, myocytes were dialyzed with effective concentrations of guanine nucleotides.(ABSTRACT TRUNCATED AT 250 WORDS)
ESTHER : Shirayama_1993_J.Pharmacol.Exp.Ther_265_641
PubMedSearch : Shirayama_1993_J.Pharmacol.Exp.Ther_265_641
PubMedID: 8388456

Title : Carbachol activates a novel sodium current in isolated guinea pig ventricular myocytes via M2 muscarinic receptors - Matsumoto_1991_Mol.Pharmacol_39_359
Author(s) : Matsumoto K , Pappano AJ
Ref : Molecular Pharmacology , 39 :359 , 1991
Abstract : Carbachol induces a novel tetrodotoxin-resistant Na+ current in guinea pig ventricular myocytes bathed in Tyrode's solution with 20 mM Cs+. This action of carbachol, which initiates a series of reactions that culminates in a catecholamine-independent positive inotropic effect, occurs through muscarinic rather than nicotinic cholinoceptive sites. The concentrations of muscarinic antagonists required to suppress the carbachol-induced current by 50% were 2.1 nM, 270 nM, and 1700 nM for atropine, AF-DX 116, and pirenzepine, respectively. These results indicate that an M2-selective antagonist, AF-DX 116, is more potent than an M1-selective antagonist, pirenzepine, as an inhibitor. The M1-selective agonist McN-A-343 did not induce an inward current and blocked that caused by carbachol, in a rapid and reversible manner. This finding is also consistent with the conclusion that the muscarinic receptor involved in the regulation of myocardial Na+ channels by carbachol cannot be distinguished from the M2 subtype of such receptors. Treatment with pertussis toxin did not affect the ability of carbachol to induce an inward current in ventricular myocytes and reversed the current activated by carbachol in atrial cells from outward to inward. The electrophysiological and pharmacological nature of the carbachol-induced current in ventricular myocytes is very similar to that of the acetylcholine-induced current in Xenopus oocytes transfected with porcine M2, but not M1, muscarinic receptors. In both preparations, Na+ is the dominant charge carrier, intracellular Ca2+ is not involved in opening the Na+ channel, and an M2 receptor is involved.
ESTHER : Matsumoto_1991_Mol.Pharmacol_39_359
PubMedSearch : Matsumoto_1991_Mol.Pharmacol_39_359
PubMedID: 1706471

Title : Carbachol depolarizes and evokes an inward current in heart muscle: a novel action of muscarinic agonist -
Author(s) : Pappano AJ , Matsumoto K , Meszaros J , Tanaka M
Ref : Prog Clin Biol Res , 334 :313 , 1990
PubMedID: 2309008

Title : Sodium-dependent membrane current induced by carbachol in single guinea-pig ventricular myocytes - Matsumoto_1989_J.Physiol_415_487
Author(s) : Matsumoto K , Pappano AJ
Ref : Journal of Physiology , 415 :487 , 1989
Abstract : 1. In the presence of either barium (0.2 mM) or caesium (20 mM), carbachol (3-300 microM) depolarized isolated guinea-pig ventricular myocytes. Carbachol induced an inward current under voltage clamp at a holding potential equal to the resting potential (-75 mV). 2. Acetylcholine and oxotremorine also evoked an inward current but were less effective than carbachol. Atropine (0.3 microM) prevented the depolarization and inward current induced by carbachol and acetylcholine but not by oxotremorine. Moreover, oxotremorine, but not carbachol, induced an inward current in the absence of extracellular sodium. 3. Carbachol increased membrane chord conductance when it induced an inward current. These effects were recorded under experimental conditions that suppressed the voltage- and time-dependent sodium current (tetrodotoxin) and calcium current (cadmium), the inwardly rectifying potassium current, iK1 (caesium, barium and tetraethylammonium) and the current generated by the sodium-potassium pump (zero external potassium). 4. Under these same experimental conditions, the steady-state I-V relationship in the presence of carbachol was subtracted from that in its absence. The apparent reversal potential (Erev) was 25 mV with extracellular Na+ ([ Na+]o) at 143 mM and intracellular Na+ ([Na+]i) at 11 mM. Replacement of [Na+]o by N-methyl-D-glucamine was associated with a shift of the apparent Erev to more negative voltages by approximately 61 mV per tenfold change of [Na+]o. 5. Isoprenaline induced an inward current in ventricular myocytes that depended upon sodium entry, required the accumulation of cyclic AMP and which was partially suppressed by acetylcholine (Egan, Noble, Noble, Powell, Twist & Yamaoka, 1988). In contrast to the current evoked by beta-adrenoceptor agonist, the current induced by muscarinic agonist was smaller and sustained. Moreover, the carbachol-induced current was not suppressed by prior addition of isoprenaline. 6. The findings are consistent with the mechanism that carbachol activates a plasma membrane ion channel that admits sodium and thereby increases intracellular sodium activity. The estimated increase of intracellular sodium activity from electrophysiological data agrees quantitatively with that obtained from measurements with sodium-sensitive microelectrodes (Korth & Kuhlkamp, 1985). 7. The ability of carbachol to increase sodium influx may be the first step in a series of reactions that eventually alters sodium-calcium exchange and could account for catecholamine-independent stimulation of developed force in mammalian ventricle.
ESTHER : Matsumoto_1989_J.Physiol_415_487
PubMedSearch : Matsumoto_1989_J.Physiol_415_487
PubMedID: 2561791

Title : Poster: Carbachol induces an inward Na+ current in ventricular myocytes by activating M2 muscarinic receptors -
Author(s) : Pappano AJ , Matsumoto K
Ref : Trends in Pharmacological Sciences , Suppl :100 , 1989

Title : Pertussis toxin-insensitive mechanism for carbachol-induced depolarization and positive inotropic effect in heart muscle -
Author(s) : Pappano AJ , Matsumoto K , Tajima T , Agnarsson U , Webb W
Ref : Trends in Pharmacological Sciences , Suppl :35 , 1988
PubMedID: 3074534