Nabeshima T

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Full name : Nabeshima Toshitaka

First name : Toshitaka

Mail : Department of Chemical Pharmacology, Meijo University, Graduate School of Pharmaceutical Science, Nagoya

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Country : Japan

Email : tnabeshi@ccmfs.meijo-u.ac.jp

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References (29)

Title : Effects of galantamine on social interaction impairments in cholecystokinin receptor-2 overexpression mice - Tanase_2022_J.Pharmacol.Sci_148_364
Author(s) : Tanase S , Mamiya T , Nagata S , Ikawa Y , Tang YP , Hiramatsu M , Nabeshima T
Ref : J Pharmacol Sci , 148 :364 , 2022
Abstract : We examined whether galantamine (GAL), a cholinesterase inhibitor and allosteric potentiating ligand for alpha7 nicotinic acetylcholine receptor (nAChR), had an impact on emotional abnormalities in forebrain-specific cholecystokinin receptor-2 overexpressed transgenic mice. Treatment with GAL (1 mg/kg, s.c.) attenuated the decrease of social interaction time, but failed to attenuate anxiety-like behavior in the elevated plus-maze test. The effect of GAL was blocked by an alpha7 nAChR antagonist, methyllycaconitine (3 mg/kg, i.p.). These results suggest that GAL improved social interaction impairments via alpha7 nAChR and could be useful to treat sociability-related emotional abnormalities.
ESTHER : Tanase_2022_J.Pharmacol.Sci_148_364
PubMedSearch : Tanase_2022_J.Pharmacol.Sci_148_364
PubMedID: 35300811

Title : An adenoviral vector encoded with the GPx-1 gene attenuates memory impairments induced by beta-amyloid (1-42) in GPx-1 KO mice via activation of M1 mAChR-mediated signaling - Shin_2020_Free.Radic.Res__1
Author(s) : Shin EJ , Lee SH , Sharma N , Nguyen BT , Chung YH , Kang SW , Nah SY , Lee YJ , Nabeshima T , Jeong JH , Kim HC
Ref : Free Radical Research , :1 , 2020
Abstract : In the present study, we examined whether glutathione peroxidase-1 (GPx-1), a major H(2)O(2) scavenger in the brain, affects memory deficits induced by Abeta (1-42) in mice. Treatment with 400 pmol/5 l Abeta (1-42) (i.c.v.) resulted in a reduction of GPx-1 expression in wild type (WT) mice. An Abeta (1-42)-induced reduction in acetylcholine (ACh) level was observed in the hippocampus. Treatment with Abeta (1-42) consistently resulted in reduced expression and activity of choline acetyltransferase (ChAT) and in an increase in expression and activity of acetylcholinesterase (AChE). Upon examining each of the muscarinic acetylcholine receptors (mAChRs) and nicotinic AChRs, we noted that Abeta (1-42) treatment selectively reduced the levels of M1 mAChR. In addition, Abeta (1-42) induced a significant reduction in phospho-cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) expression. The cholinergic impairments induced by Abeta (1-42) were more pronounced in GPx-1 knockout mice than in WT mice. Importantly, an adenoviral vector encoded with the GPx-1 gene (Ad-GPx-1) significantly rescued Abeta (1-42)-induced cholinergic impairments in GPx-1 knockout mice. In addition, M1 mAChR antagonist dicyclomine significantly counteracted Ad-GPx-1-mediated increases in p-CREB and BDNF expression, as well as memory-enhancing effects in GPx-1 knockout mice, thus indicating that M1 mAChR might be a critical mediator for the rescue effects of Ad-GPx-1. Combined, our results suggest that GPx-1 gene protected against Abeta (1-42)-induced memory impairments via activation of M1 mAChR-dependent CREB/BDNF signaling.
ESTHER : Shin_2020_Free.Radic.Res__1
PubMedSearch : Shin_2020_Free.Radic.Res__1
PubMedID: 33222572

Title : Galantamine improves enhanced impulsivity, impairments of attention and long-term potentiation induced by prenatal nicotine exposure to mice - Mamiya_2020_Biochem.Pharmacol__114139
Author(s) : Mamiya T , Tanase S , Takeuchi S , Kato S , Ito A , Hiramatsu M , Nabeshima T
Ref : Biochemical Pharmacology , :114139 , 2020
Abstract : Prenatal nicotine exposure (PNE) causes behavioral abnormalities in offspring, such as an enhancement of impulsivity and decrease in attention at adolescence. Here we examined the effects of galantamine (GAL) on the behavioral and electrophysiological changes induced by PNE in mice. Pregnant C57BL/6J mice were exposed to nicotine (0.2 mg/mL) dissolved in sweetened (2% saccharin) drinking water during gestational day 14 and perinatal day 0 (P0). At the ages of postnatal days 42-49 (P42-P49), female offspring displayed impulsivity in the cliff avoidance test and impairment of visual attention in the object-based attention test. Decrease of long-term potentiation (LTP) and extracellular glutamate levels were observed in the prefrontal cortex of PNE mice. Systemic treatment with GAL (1 mg/kg, s.c.), an allosteric potentiating ligand for the nicotinic acetylcholine receptor (nAChR) and a weak cholinesterase inhibitor, attenuated the enhancement of impulsivity and impairment of attention induced by PNE in mice. Further, GAL reversed the impairment of LTP induced by PNE in the prefrontal cortex of mice, although it failed to attenuate the decrease of extracellular glutamate levels. The effects of GAL were blocked by an alpha 7 nAChR antagonist, methyllycaconitine (1 mg/kg, i.p.). These results suggest that PNE during cortex development affects nicotinic cholinergic-dependent plasticity and formation of impulsivity and attention. Furthermore, GAL could be a useful drug for cognitive impairments-related to attention deficit hyperactivity disorder.
ESTHER : Mamiya_2020_Biochem.Pharmacol__114139
PubMedSearch : Mamiya_2020_Biochem.Pharmacol__114139
PubMedID: 32652142

Title : IL-6 attenuates trimethyltin-induced cognitive dysfunction via activation of JAK2\/STAT3, M1 mAChR and ERK signaling network - Kim_2013_Cell.Signal_25_1348
Author(s) : Kim BK , Tran HY , Shin EJ , Lee C , Chung YH , Jeong JH , Bach JH , Kim WK , Park DH , Saito K , Nabeshima T , Kim HC
Ref : Cell Signal , 25 :1348 , 2013
Abstract : We previously reported that interleukin (IL)-6 deficiency potentiates trimethyltin (TMT)-induced convulsive neurotoxicity. The purpose in this study was to investigate the molecular mechanism by which cytokines affect TMT-induced cognitive impairment. To accomplish this, we examined hippocampal changes in Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling in relation to cholinergic parameters after TMT treatment in mice genetically deficient in IL-6 (IL-6(-/-)), tumor necrosis factor-alpha (TNF-alpha(-/-)), or interferon-gamma (IFN-gamma(-/-)). The IL-6(-/-) mice were the most susceptible to TMT-induced cognitive dysfunction and exhibited significant decreases in JAK2/STAT3 signaling and M1 muscarinic acetylcholine receptor (mAChR) expression, as well as other cholinergic parameters, compared with wild-type (WT) animals. Recombinant IL-6 protein (rIL-6) significantly attenuated these impairments in TMT-treated IL-6(-/-) mice, whereas an IL-6 receptor antibody potentiated these impairments in TMT-treated WT animals. Inhibition of JAK2 with AG490 or inhibition of cholinergic signaling with the M1 mAChR antagonist dicyclomine counteracted the attenuating effects of rIL-6 on phosphorylated extracellular signal-regulated kinase (ERK) expression, or on cognitive impairment in TMT-treated IL-6(-/-) mice. However, neither AG490 nor dicyclomine significantly attenuated effects of rIL-6 on acetylcholinesterase values. Our results suggest that activation of JAK2/STAT3 signaling and upregulation of the M1 mAChR are essential components of IL-6-mediated memory improvement against TMT toxicity.
ESTHER : Kim_2013_Cell.Signal_25_1348
PubMedSearch : Kim_2013_Cell.Signal_25_1348
PubMedID: 23499905

Title : Inactivation of JAK2\/STAT3 signaling axis and downregulation of M1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging - Park_2013_Neuropsychopharmacology_38_1426
Author(s) : Park SJ , Shin EJ , Min SS , An J , Li Z , Hee Chung Y , Hoon Jeong J , Bach JH , Nah SY , Kim WK , Jang CG , Kim YS , Nabeshima Y , Nabeshima T , Kim HC
Ref : Neuropsychopharmacology , 38 :1426 , 2013
Abstract : We previously reported cognitive dysfunction in klotho mutant mice. In the present study, we further examined novel mechanisms involved in cognitive impairment in these mice. Significantly decreased janus kinase 2 (JAK2) and signal transducer and activator of transcription3 (STAT3) phosphorylation were observed in the hippocampus of klotho mutant mice. A selective decrease in protein expression and binding density of the M1 muscarinic cholinergic receptor (M1 mAChR) was observed in these mice. Cholinergic parameters (ie, acetylcholine (ACh), choline acetyltransferase (ChAT), and acetylcholinesterase (AChE)) and NMDAR-dependent long-term potentiation (LTP) were significantly impaired in klotho mutant mice. McN-A-343 (McN), an M1 mAChR agonist, significantly attenuated these impairments. AG490 (AG), a JAK2 inhibitor, counteracted the attenuating effects of McN, although AG did not significantly alter the McN-induced effect on AChE. Furthermore, AG significantly inhibited the attenuating effects of McN on decreased NMDAR-dependent LTP, protein kinase C betaII, p-ERK, p-CREB, BDNF, and p-JAK2/p-STAT3-expression in klotho mutant mice. In addition, k252a, a BDNF receptor tyrosine kinase B (TrkB) inhibitor, significantly counteracted McN effects on decreased ChAT, ACh, and M1 mAChR and p-JAK2/p-STAT3 expression. McN-induced effects on cognitive impairment in klotho mutant mice were consistently counteracted by either AG or k252a. Our results suggest that inactivation of the JAK2/STAT3 signaling axis and M1 mAChR downregulation play a critical role in cognitive impairment observed in klotho mutant mice.
ESTHER : Park_2013_Neuropsychopharmacology_38_1426
PubMedSearch : Park_2013_Neuropsychopharmacology_38_1426
PubMedID: 23389690

Title : Galantamine ameliorates the impairment of recognition memory in mice repeatedly treated with methamphetamine: involvement of allosteric potentiation of nicotinic acetylcholine receptors and dopaminergic-ERK1\/2 systems - Noda_2010_Int.J.Neuropsychopharmacol_13_1343
Author(s) : Noda Y , Mouri A , Ando Y , Waki Y , Yamada SN , Yoshimi A , Yamada K , Ozaki N , Wang D , Nabeshima T
Ref : Int J Neuropsychopharmacol , 13 :1343 , 2010
Abstract : Galantamine, a drug used to treat Alzheimer's disease, inhibits acetylcholinesterase (AChE) and allosterically modulates nicotinic acetylcholine receptors (nAChRs) resulting in stimulation of catecholamine neurotransmission. In this study, we investigated whether galantamine exerts cognitive-improving effects through the allosteric modulation of nAChRs in an animal model of methamphetamine (Meth) psychosis. The mice treated with Meth (1 mg/kg.d) for 7 d showed memory impairment in a novel object recognition test. Galantamine (3 mg/kg) ameliorated the memory impairment, and it increased the extracellular dopamine release in the prefrontal cortex (PFC) of Meth-treated mice. Donepezil, an AChE inhibitor (1 mg/kg) increased the extracellular ACh release in the PFC, whereas it had no effect on the memory impairment in Meth-treated mice. The nAChR antagonist, mecamylamine, and dopamine D1 receptor antagonist, SCH 23390, blocked the ameliorating effect of galantamine on Meth-induced memory impairment, whereas the muscarinic AChR antagonist, scopolamine, had no effect. The effects of galantamine on extracellular dopamine release were also antagonized by mecamylamine. Galantamine attenuated the defect of the novelty-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2). The ameliorating effect of galantamine on recognition memory in Meth-treated mice was negated by microinjection of an ERK inhibitor, PD98059, into the PFC. These results suggest that the ameliorating effect of galantamine on Meth-induced memory impairment is associated with indirect activation of dopamine D1 receptor-ERK1/2 following augmentation with dopaminergic neurotransmission in the PFC through the allosteric activation of nAChRs. Galantamine could be a useful therapeutic agent for treating cognitive deficits in schizophrenia/Meth psychosis, as well as Alzheimer's disease.
ESTHER : Noda_2010_Int.J.Neuropsychopharmacol_13_1343
PubMedSearch : Noda_2010_Int.J.Neuropsychopharmacol_13_1343
PubMedID: 20219155

Title : Growth hormone-releaser diet attenuates beta-amyloid(1-42)-induced cognitive impairment via stimulation of the insulin-like growth factor (IGF)-1 receptor in mice - Shin_2009_J.Pharmacol.Sci_109_139
Author(s) : Shin EJ , Chae JS , Park SJ , Kim SC , Koo KH , Yamada K , Nabeshima T , Kim HC
Ref : J Pharmacol Sci , 109 :139 , 2009
Abstract : We previously demonstrated that the growth hormone (GH)-releaser diet ameliorated beta-amyloid (A beta) (1-42)-induced memory impairment, but the underlying mechanism remained to be characterized. We show here that the GH-releaser diet significantly attenuated A beta(1-42)-induced impairment in context-dependent conditioned fear, with a reduction in GH levels and changes in hippocampal acetylcholine, acetylcholinesterase, choline acetyltransferase, insulin-like growth factor (IGF)-1, and IGF-1-receptor activity in mice. JB-1, an IGF-1-receptor antagonist, significantly blocked GH-releaser diet-mediated pharmacological actions. Our results suggest that the GH-releaser diet prevents A beta(1-42)-induced cognitive deficits via stimulation of the hippocampal IGF-1 receptor.
ESTHER : Shin_2009_J.Pharmacol.Sci_109_139
PubMedSearch : Shin_2009_J.Pharmacol.Sci_109_139
PubMedID: 19151546

Title : Fustin flavonoid attenuates beta-amyloid (1-42)-induced learning impairment - Jin_2009_J.Neurosci.Res_87_3658
Author(s) : Jin CH , Shin EJ , Park JB , Jang CG , Li Z , Kim MS , Koo KH , Yoon HJ , Park SJ , Choi WC , Yamada K , Nabeshima T , Kim HC
Ref : Journal of Neuroscience Research , 87 :3658 , 2009
Abstract : Natural flavonoids ameliorate amyloid-beta peptide (Abeta)-induced neurotoxicity. We examined whether the fustin flavonoid affects Abeta-induced learning impairment in mice. Repeated treatment with fustin significantly attenuated Abeta (1-42)-induced conditioned fear and passive avoidance behaviors. This effect was comparable to that of EGb761, a standard extract of ginkgo. Fustin treatment significantly prevented decreases in acetylcholine (ACh) levels, choline acetyltransferase (ChAT) activity, and ChAT gene expression induced by Abeta (1-42). Fustin also consistently suppressed increases in acetyl cholinesterase (AChE) activity and AChE gene expression induced by Abeta (1-42). In addition, fustin significantly attenuated Abeta (1-42)-induced selective decreases in muscarinic M1 receptor gene expression and muscarinic M1 receptor binding activity (as determined by [(3)H]pirenzepine binding) by modulating extracellular signal-regulated kinase 1/2 (ERK 1/2) and cAMP response-element binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) expression. These effects of fustin were reversed by treatment with dicyclomine, a muscarinic M1 receptor antagonist, and SL327, a selective ERK inhibitor, but not by chelerythrine, a pan-protein kinase C (PKC) inhibitor. Taken together, our results suggest that fustin attenuates Abeta (1-42)-impaired learning, and that the ERK/CREB/BDNF pathway is important for the M1 receptor-mediated cognition-enhancing effects of fustin.
ESTHER : Jin_2009_J.Neurosci.Res_87_3658
PubMedSearch : Jin_2009_J.Neurosci.Res_87_3658
PubMedID: 19533734

Title : Discontinuation of donepezil for the treatment of Alzheimer's disease in geriatric practice - Umegaki_2008_Int.Psychogeriatr_20_800
Author(s) : Umegaki H , Itoh A , Suzuki Y , Nabeshima T
Ref : Int Psychogeriatr , 20 :800 , 2008
Abstract : BACKGROUND: Maintaining continuous pharmacological treatment of patients with dementia is often difficult. In the current study we surveyed the discontinuation of donepezil, a cholinesterase inhibitor, for the treatment of Alzheimer's disease in a Japanese geriatric outpatient clinic in a university hospital. METHODS: Using a retrospective chart review from 1 July 2003 to 30 June 2005, prescriptions of donepezil and the reasons for discontinuing the prescription in a university hospital were determined. The severity of dementia was evaluated by the clinical dementia rating (CDR). RESULTS: Out of 264 patients, 140 (53.1%) discontinued taking donepezil during the two-year observation period. The mean age of the continued group and the discontinued group did not differ significantly (79.5 +/- 6.7, 79.8 +/- 6.4, respectively). Kaplan-Meier analysis showed that the patients with more severe cognitive impairment (CDR score = 3) discontinued donepezil earlier and more frequently. The reasons for discontinuation were a change in the doctors treating the patients (n = 71), ineffectiveness (n = 16), gastrointestinal side-effects (n = 11), and others (n = 41). In patients with CDR = 1 or 2, changes of doctors were the most frequent reason for discontinuation. However, in patients with CDR = 3, ineffectiveness of the medication was the major reason for discontinuation. CONCLUSION: Donepezil was frequently discontinued, and the rate of discontinuation was higher in patients with advanced dementia.
ESTHER : Umegaki_2008_Int.Psychogeriatr_20_800
PubMedSearch : Umegaki_2008_Int.Psychogeriatr_20_800
PubMedID: 18341753

Title : Synergistic effects of selegiline and donepezil on cognitive impairment induced by amyloid beta (25-35) - Tsunekawa_2008_Behav.Brain.Res_190_224
Author(s) : Tsunekawa H , Noda Y , Mouri A , Yoneda F , Nabeshima T
Ref : Behavioural Brain Research , 190 :224 , 2008
Abstract : Selegiline, an irreversible inhibitor of monoamine oxidase B used in the treatment of Parkinson's disease, has been demonstrated to have a potential cognition-improving effect in patients with Alzheimer's disease (AD) undergoing treatment with an acetylcholinesterase inhibitor donepezil. To confirm such clinical events, we investigated whether co-administration of donepezil with selegiline had a synergistic cognition-improving effect in an animal model of AD. Intracerebroventricular injection of amyloid beta protein fragment 25-35 [Abeta(25-35)] induced impairment of learning and memory in a Y-maze, novel object recognition and contextual fear conditioning tests. Either donepezil or selegiline alone improved the cognitive impairments in the Y-maze and conditioned fear learning tasks in Abeta(25-35)-injected mice, whereas donepezil, but not selegiline, failed to improve the impairment in a novel object recognition task. Co-administration of donepezil with selegiline, at doses that do not exert efficacy individually, significantly improved the deficits in all three tests, indicating a synergistic cognition-improving effect. These alleviating effects were antagonized by pretreatment with a muscarinic receptor antagonist scopolamine and a dopamine receptor antagonist haloperidol. These results suggest that selegiline potentiates the effect of donepezil on the cognitive impairment, and that the synergistic effect may be mediated through both the cholinergic and dopaminergic systems.
ESTHER : Tsunekawa_2008_Behav.Brain.Res_190_224
PubMedSearch : Tsunekawa_2008_Behav.Brain.Res_190_224
PubMedID: 18420288

Title : The allosteric potentiation of nicotinic acetylcholine receptors by galantamine ameliorates the cognitive dysfunction in beta amyloid25-35 i.c.v.-injected mice: involvement of dopaminergic systems - Wang_2007_Neuropsychopharmacology_32_1261
Author(s) : Wang D , Noda Y , Zhou Y , Mouri A , Mizoguchi H , Nitta A , Chen W , Nabeshima T
Ref : Neuropsychopharmacology , 32 :1261 , 2007
Abstract : Galantamine, a drug for Alzheimer's disease, is a novel cholinergic agent with a dual mode of action, which inhibits acetylcholinesterase and allosterically modulates nicotinic acetylcholine receptors (nAChRs), as a result stimulates catecholamine neurotransmission. In the present study, we investigated whether galantamine exerts cognitive improving effects through the allosteric modulation of nAChR in the intracerebroventricular beta amyloid (Abeta)(25-35)-injected animal model of Alzheimer's disease. Galantamine (3 mg/kg p.o.) significantly increased the extracellular dopamine release in the hippocampus of saline- and Abeta(25-35)-injected mice. The effects of nicotine on the extracellular dopamine release were potentiated by galantamine, but antagonized by mecamylamine, a nAChR antagonist. Abeta(25-35)-injected mice, compared with saline-injected mice, could not discriminate between new and familiar objects in the novel object recognition test and exhibited less freezing response in the fear-conditioning tasks, suggesting Abeta(25-35) induced cognitive impairment. Galantamine improved the Abeta(25-35)-induced cognitive impairment in the novel object recognition and fear-conditioning tasks. These improving effects of galantamine were blocked by the treatment with mecamylamine, SCH-23390, a dopamine-D1 receptor antagonist, and sulpiride, a dopamine-D2 receptor antagonist, but not by scopolamine, a muscarinic acetylcholine receptor antagonist. This study provides the first in vivo evidence that galantamine augments dopaminergic neurotransmission within the hippocampus through the allosteric potentiation of nAChRs. The improving-effects of galantamine on the Abeta(25-35)-induced cognitive impairment may be mediated through the activation of, at least in part, dopaminergic systems, and the enhancement of dopamine release may be one of multiple mechanisms underlying the therapeutic benefit of galantamine.
ESTHER : Wang_2007_Neuropsychopharmacology_32_1261
PubMedSearch : Wang_2007_Neuropsychopharmacology_32_1261
PubMedID: 17133263

Title : Synergistic effect of galantamine with risperidone on impairment of social interaction in phencyclidine-treated mice as a schizophrenic animal model - Wang_2007_Neuropharmacol_52_1179
Author(s) : Wang D , Noda Y , Zhou Y , Nitta A , Furukawa H , Nabeshima T
Ref : Neuropharmacology , 52 :1179 , 2007
Abstract : Social withdrawal is the first sign and key component of the negative symptoms of schizophrenia. The efficacy of risperidone, an atypical antipsychotic, on the symptom is practically limited by dose-dependent side effects in clinical trials, therefore there is the need for adjuvant treatments. In the present study, we aimed to investigate the synergistic effect and mechanism of risperidone and galantamine, which is a nicotinic acetylcholine receptor (nAChR)-allosteric modulator and a modest cholinesterase inhibitor, on phencyclidine (PCP)-treated mouse model of social withdrawal. At non-effective doses by themselves, co-administration of galantamine (0.05mg/kg) and risperidone (0.05mg/kg) showed synergistic effects on PCP-induced impairments of social interaction and dopamine release in the medial prefrontal cortex (mPFC). The behavioral synergistic effect was abolished by the administration of a dopamine-D(1) receptor antagonist, SCH 23390 (0.02mg/kg, systemic; or 0.02microg/0.5microL/mouse, intra-mPFC), and a nAChR antagonist, mecamylamine (3mg/kg), but not a muscarinic receptor antagonist, scopolamine (0.1mg/kg). Mecamylamine (3mg/kg) also abolished the synergistic effect on dopamine release in the mPFC. We conclude that galantamine may have synergistic effect with risperidone on the negative symptom of social withdrawal in schizophrenia, which is mediated by dopamine-D(1) receptors in the mPFC through nAChR activation-increased dopamine release.
ESTHER : Wang_2007_Neuropharmacol_52_1179
PubMedSearch : Wang_2007_Neuropharmacol_52_1179
PubMedID: 17313962

Title : Synergistic effect of combined treatment with risperidone and galantamine on phencyclidine-induced impairment of latent visuospatial learning and memory: Role of nAChR activation-dependent increase of dopamine D1 receptor-mediated neurotransmission - Wang_2007_Neuropharmacol_53_379
Author(s) : Wang D , Noda Y , Zhou Y , Nitta A , Furukawa H , Nabeshima T
Ref : Neuropharmacology , 53 :379 , 2007
Abstract : The clinically achievable efficacy of the atypical antipsychotics on cognitive symptoms of schizophrenia is practically limited by their dose-dependent side effects. Thus, there is the need for adjuvant treatments or strategies for the cognitive impairments. Further, human autopsy and genetic data in schizophrenia have indicated the existence of the abnormality of nicotinic acetylcholine receptors (nAChR). In the present study, we aimed to investigate the synergistic effect and mechanisms of a combined treatment with an atypical antipsychotic risperidone and galantamine, which is a nAChR-allosteric modulator and a modest cholinesterase inhibitor, on the impairment of latent visuospatial learning and memory in mice resembling the cognitive impairment of schizophrenia. Repeated treatment with phencyclidine (PCP, 10 mg/kg, 14 days)-induced cognitive impairment in mice in a one trial water-finding test was used as a model of the cognitive impairment of schizophrenia. In vivo microdialysis was used to investigate the extracellular concentration of dopamine in the medial prefrontal cortex (mPFC). Combined treatment with galantamine and risperidone, at low, ineffective doses (both at 0.05 mg/kg) showed a synergistic effect to reverse cognitive impairment and increase extracellular concentration of dopamine in the mPFC. The synergistic behavioral effect was abolished by a dopamine-D1 receptor antagonist, SCH 23390, and a nAChR antagonist, mecamylamine, but not a muscarinic AChR (mAChR) antagonist, scopolamine. Mecamylamine also blocked the synergistic effect on dopamine release in the mPFC of PCP-treated mice. The study indicates that galantamine and risperidone may have synergistic effect on the cognitive impairments in schizophrenia patients by synergistically promoting the nAChR activation-dependent increase of dopamine D1 receptor-mediated neurotransmission.
ESTHER : Wang_2007_Neuropharmacol_53_379
PubMedSearch : Wang_2007_Neuropharmacol_53_379
PubMedID: 17632185

Title : Growth hormone releaser attenuates beta-amyloid (1 - 42)-induced memory impairment in mice - Shin_2005_J.Pharmacol.Sci_99_117
Author(s) : Shin EJ , Jhoo JH , Nabeshima T , Jhoo WK , Kwon MS , Lim YK , Chae JS , Jung ME , Park SJ , Jang KJ , Kim HC
Ref : J Pharmacol Sci , 99 :117 , 2005
Abstract : Accumulating evidence indicates that growth hormone (GH) might be effective at preventing the development of Alzheimer's disease. However, exogenous GH treatment has exhibited side effects for clinical application; thus supplementation with amino acids to promote the release of GH could be a possible alternative treatment. In this study, mice that were fed with a diet of GH-releasing supplements had significantly attenuated memory impairments and hippocampal changes in the acetylcholinesterase activity and acetylcholine level induced by amyloid beta protein (Abeta) (1 - 42). Our results suggest that the use of GH-releasing supplement exerts beneficial effects on the memory impairment induced by Abeta (1 - 42).
ESTHER : Shin_2005_J.Pharmacol.Sci_99_117
PubMedSearch : Shin_2005_J.Pharmacol.Sci_99_117
PubMedID: 16141634

Title : Irinotecan therapy in a 12-year-old girl with recurrent brain stem glioma and without functional polymorphisms in UGT1A1 activity: case report - Ishikawa_2005_J.Neurooncol_74_283
Author(s) : Ishikawa K , Kajita Y , Hasegawa Y , Noda Y , Yoshida J , Nabeshima T
Ref : J Neurooncol , 74 :283 , 2005
Abstract : A 10-year-old girl was diagnosed with astrocytoma grade 2. Immuno-chemo-radiotherapy (interferon, ranimustine, and radiation), second-line chemotherapy (carboplatin and etoposide, 7 cycles) and third-line chemotherapy (ifosfamide, carboplatin, and etoposide) was given to treat progressive disease. Finally, irinotecan therapy was initiated and led to dramatic clinical improvement. Irinotecan is metabolized by carboxylesterase to form an active SN-38, which is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) to yield its beta-glucuronide. The polymorphic UGT isoenzyme, UGT1A1 has genetic variants which decrease in SN-38 glucuronidating capacity and could help predict irinotecan-associated toxicity. The patient suffered excessive toxicity with low-dose irinotecan although no functional polymorphism in UGT1A1 was identified. We suggest that irinotecan offers an effective treatment option for children with recurrent brain stem glioma and other genetic variants except UGT1A1 may be a risk factor for irinotecan-induced toxicity.
ESTHER : Ishikawa_2005_J.Neurooncol_74_283
PubMedSearch : Ishikawa_2005_J.Neurooncol_74_283
PubMedID: 16187025

Title : An amino acid substitution attributable to insecticide-insensitivity of acetylcholinesterase in a Japanese encephalitis vector mosquito, Culex tritaeniorhynchus - Nabeshima_2004_Biochem.Biophys.Res.Commun_313_794
Author(s) : Nabeshima T , Mori A , Kozaki T , Iwata Y , Hidoh O , Harada S , Kasai S , Severson DW , Kono Y , Tomita T
Ref : Biochemical & Biophysical Research Communications , 313 :794 , 2004
Abstract : A cDNA sequence encoding a Drosophila Ace-paralogous acetylcholinesterase (AChE) precursor of 701 amino acid residues was identified as the second AChE gene (Ace2) transcript from Culex tritaeniorhynchus. The Ace2 gene is tightly linked to organophosphorus insecticide (OP)-insensitivity of AChE on chromosome 2. The cDNA sequences were compared between an insecticide-susceptible strain and the resistant strain, TYM, that exhibits a 870-fold decrease in fenitroxon-sensitivity of AChE. Two amino acid substitutions were present in TYM mosquitoes. One is F455W whose homologous position in Torped AChE (Phe331) is located in the vicinity of the catalytic His in the acyl pocket of the active site gorge. The other substitution is located to a C-terminal Ile697 position that apparently seems to be excluded from the mature protein and is irrelevant to catalytic activity. The F455W replacement in the Ace2 gene is solely responsible for the insecticide-insensitivity of AChE in TYM mosquitoes.
ESTHER : Nabeshima_2004_Biochem.Biophys.Res.Commun_313_794
PubMedSearch : Nabeshima_2004_Biochem.Biophys.Res.Commun_313_794
PubMedID: 14697262
Gene_locus related to this paper: cultr-ACHE1 , cultr-ACHE2

Title : Mechanism of action of aripiprazole predicts clinical efficacy and a favourable side-effect profile - Hirose_2004_J.Psychopharmacol_18_375
Author(s) : Hirose T , Uwahodo Y , Yamada S , Miwa T , Kikuchi T , Kitagawa H , Burris KD , Altar CA , Nabeshima T
Ref : J Psychopharmacol , 18 :375 , 2004
Abstract : The antipsychotic efficacy of aripiprazole is not generally associated with extrapyramidal symptoms, cardiovascular effects, sedation or elevations in serum prolactin that characterize typical or atypical antipsychotics. The aim of this study was to clarify the mechanism of action of aripiprazole that underlies its favourable clinical profiles. The preclinical efficacy and side-effect profiles of aripiprazole were evaluated using several pharmaco-behavioural test systems in mice and rats, both in vivo and ex vivo, and compared with those of other conventional and atypical antipsychotics. Each of the antipsychotics induced catalepsy and inhibited apomorphine-induced stereotypy. The catalepsy liability ratios for these drugs were 6.5 for aripiprazole, 4.7 for both olanzapine and risperidone. The ptosis liability ratios for aripiprazole, olanzapine and risperidone were 14, 7.2 and 3.3, respectively. Aripiprazole slightly increased DOPA accumulation in the forebrain of reserpinised mice, reduced 5-HTP accumulation at the highest dose and exhibited a weaker inhibition of 5-methoxy-N,N-dimethyl-tryptamine-induced head twitches. Aripiprazole did not inhibit physostigmine- or norepinephrine-induced lethality in rats. In conclusion, aripiprazole shows a favourable preclinical efficacy and side-effect profile compared to a typical antipsychotics. This profile may result from its high affinity partial agonist activity at D2 and 5-HT1A receptors and its antagonism of 5-HT2A receptors.
ESTHER : Hirose_2004_J.Psychopharmacol_18_375
PubMedSearch : Hirose_2004_J.Psychopharmacol_18_375
PubMedID: 15358981

Title : An amino acid substitution on the second acetylcholinesterase in the pirimicarb-resistant strains of the peach potato aphid, Myzus persicae - Nabeshima_2003_Biochem.Biophys.Res.Commun_307_15
Author(s) : Nabeshima T , Kozaki T , Tomita T , Kono Y
Ref : Biochemical & Biophysical Research Communications , 307 :15 , 2003
Abstract : cDNAs encoding two acetylcholinesterases (AChEs) were isolated from the peach potato aphid, Myzus persicae. MpAChE1 was orthologous and MpAChE2 was paralogous with the ace of Drosophila melanogaster. The deduced amino acid sequence of MpAChE1 cDNA was identical between the pirimicarb susceptible and resistant strains. However, a single amino acid substitution of Ser431Phe on MpAchE2 was found in the pirimicarb resistant strains. This substitution was located in the acyl pocket of the enzyme and was thought to alter the ligand specificity.
ESTHER : Nabeshima_2003_Biochem.Biophys.Res.Commun_307_15
PubMedSearch : Nabeshima_2003_Biochem.Biophys.Res.Commun_307_15
PubMedID: 12849975
Gene_locus related to this paper: myzpe-ACHE , myzpe-ACHEm

Title : Nefiracetam elevates extracellular acetylcholine level in the frontal cortex of rats with cerebral cholinergic dysfunctions: an in vivo microdialysis study - Sakurai_1998_Neurosci.Lett_246_69
Author(s) : Sakurai T , Kato T , Mori K , Takano E , Watabe S , Nabeshima T
Ref : Neuroscience Letters , 246 :69 , 1998
Abstract : We determined the effect of nefiracetam, a novel cognitive enhancer, on the extracellular acetylcholine (ACh) level in the frontal cortex of freely moving rats, using a microdialysis technique without an acetylcholinesterase inhibitor in the perfusate. Treatment with nefiracetam (10 mg/kg, p.o.) produced a significant increase in the level of ACh in the brain dialysate, compared with the vehicle-treated group. This enhancing effect was also observed when the ACh level was elevated by administration of scopolamine (1 mg/kg, i.p.) at 45 min after the treatment with nefiracetam. In addition, perfusion of nefiracetam at the concentration of 10 microM significantly increased the extracellular ACh level in the frontal cortex of basal forebrain (BF)-lesioned rats, in which a marked decrease of the basal ACh level was observed in this region. These results suggest that enhancement of cortical ACh release by nefiracetam may contribute to an anti-amnesic effect on the learning deficits induced by treatment of scopolamine or BF-lesion in rats.
ESTHER : Sakurai_1998_Neurosci.Lett_246_69
PubMedSearch : Sakurai_1998_Neurosci.Lett_246_69
PubMedID: 9627182

Title : Effects of metrifonate on impairment of learning and dysfunction of cholinergic neuronal system in basal forebrain-lesioned rats - Itoh_1997_Behav.Brain.Res_83_165
Author(s) : Itoh A , Nitta A , Hirose M , Hasegawa T , Nabeshima T
Ref : Behavioural Brain Research , 83 :165 , 1997
Abstract : Several studies have indicated the possibility of using cholinesterase (ChE) inhibitors as therapeutic drugs for Alzheimer's disease. Metrifonate (MTF) is an organophosphorus compound that has been used in the treatment of schistosomiasis. In this study, we investigated the effects of MTF on the impairment of learning and memory, decreased ChE activity and extracellular acetylcholine (ACh) levels in basal forebrain (BF)-lesioned rats. The oral administration of MTF improved the BF-lesion-induced impairment of performance on passive avoidance task. Further, MTF reduced ChE activity in the cerebral cortex. In vivo brain microdialysis studies showed that MTF significantly increased the release of ACh, but decreased that of choline (Ch) in the cerebral cortex of BF-lesioned rats. These results indicated that MTF ameliorates the impairment of performance on passive avoidance task in BF-lesioned rats by increasing the extracellular ACh levels by inhibiting ChE. This suggested that MTF may be useful as a therapeutic drug for Alzheimer's disease.
ESTHER : Itoh_1997_Behav.Brain.Res_83_165
PubMedSearch : Itoh_1997_Behav.Brain.Res_83_165
PubMedID: 9062677

Title : Effects of metrifonate on memory impairment and cholinergic dysfunction in rats - Itoh_1997_Eur.J.Pharmacol_322_11
Author(s) : Itoh A , Nitta A , Katono Y , Usui M , Naruhashi K , Iida R , Hasegawa T , Nabeshima T
Ref : European Journal of Pharmacology , 322 :11 , 1997
Abstract : Metrifonate is an organophosphorous compound that has been used in the treatment of schistosomiasis. In this study, we investigated the effects of metrifonate on the impairment of learning and on central cholinergic dysfunction in scopolamine-treated and basal forebrain-lesioned rats. Oral administration of metrifonate (5.0-15.0 mg/kg) ameliorated the scopolamine- and basal forebrain. lesion-induced learning impairment in the water maze and passive avoidance tasks. Metrifonate (50 and 100 mg/kg) also significantly increased extracellular acetylcholine levels but decreased choline levels in the cerebral cortex of the basal forebrain-lesioned rats. The basal forebrain lesion decreased the cholinesterase activity in the cerebral cortex, and metrifonate (100 mg/kg) further reduced the cholinesterase activity. However, cholinesterase inhibition was not observed at the dose that ameliorated learning impairments. These results indicated that metrifonate ameliorated the impairment of learning in both scopolamine-treated and basal forebrain-lesioned rats by not only increasing extracellular acetylcholine levels by inhibiting cholinesterase, but also by undefined other mechanism(s). This finding suggests the usefulness of metrifonate for the therapy of Alzheimer's disease.
ESTHER : Itoh_1997_Eur.J.Pharmacol_322_11
PubMedSearch : Itoh_1997_Eur.J.Pharmacol_322_11
PubMedID: 9088864

Title : Age-related changes in learning and memory and cholinergic neuronal function in senescence accelerated mice (SAM) - Nitta_1995_Behav.Brain.Res_72_49
Author(s) : Nitta A , Naruhashi K , Umemura M , Hasegawa T , Furukawa S , Sekiguchi F , Ishibashi K , Nabeshima T
Ref : Behavioural Brain Research , 72 :49 , 1995
Abstract : The senescence-accelerated mouse (SAM) has been established as a murine model of accelerated aging. We investigated learning ability and memory in various tasks in a SAM strain, SAMP1TA, and in a control strain of SAMR1TA at the ages of 20, 30 and 40 weeks. We also measured choline acetyltransferase (ChAT) and cholinesterase (ChE) activity in the brains of these mice at the same ages. In a Y-maze task, in which short-term memory can be examined, there was no difference in learning ability between SAMP1TA and SAMR1TA at any age. Ability in latent learning and passive-avoidance tasks was less in SAMP1TA at 30 weeks of age than in age-matched SAMR1TA. The level of ChAT activity in the striatum of SAMP1TA was lower, than that of SAMR1TA at the ages of 20 and 30 weeks. At the ages of 40 and 50 weeks, ChE activity in the striatum of SAMP1TA was lower than that of SAMR1TA. These results suggest that SAMP1TA has a deficit, with cholinergic neuronal dysfunction, in learning ability and memory, as shown by impairment of performance in latent learning and long-term memory, but not in short-term memory.
ESTHER : Nitta_1995_Behav.Brain.Res_72_49
PubMedSearch : Nitta_1995_Behav.Brain.Res_72_49
PubMedID: 8788856

Title : Memory impairment and neuronal dysfunction induced by beta-amyloid protein in rats - Nabeshima_1994_Tohoku.J.Exp.Me_174_241
Author(s) : Nabeshima T , Nitta A
Ref : Tohoku Journal of Experimental Medicine , 174 :241 , 1994
Abstract : Alzheimer's disease (AD) is characterized by the presence of senile plaques. The core of the plaque consists of beta-amyloid protein. In AD patients, learning and memory are impaired with a concomitant loss of the cholinergic marker enzyme, choline acetyltransferase (ChAT). However, direct evidence that beta-amyloid protein is related to the impairment of learning and memory has not been demonstrated. In this study, we investigated whether memory impairment and neuronal dysfunction were produced after 2 weeks continuous infusion of beta-amyloid protein (3, 30 and 300 pmol/day) into the cerebral ventricles in adult rats. To investigate the ability of learning and memory in beta-amyloid protein-treated rats, water maze and passive avoidance tasks were carried out. The performance of both tasks in beta-amyloid protein-treated rats was impaired. ChAT activity in the frontal cortex (3 and 30 pmol/day) and hippocampus (300 pmol/day) significantly decreased. These results suggest that beta-amyloid protein is related to the impairment of learning and memory, and neurodegeneration, and that beta-amyloid protein-treated rats could be used as an animal model for AD.
ESTHER : Nabeshima_1994_Tohoku.J.Exp.Me_174_241
PubMedSearch : Nabeshima_1994_Tohoku.J.Exp.Me_174_241
PubMedID: 7761989

Title : Memory impairment and neural dysfunction after continuous infusion of anti-nerve growth factor antibody into the septum in adult rats - Nitta_1993_Neurosci_57_495
Author(s) : Nitta A , Murase K , Furukawa Y , Hayashi K , Hasegawa T , Nabeshima T
Ref : Neuroscience , 57 :495 , 1993
Abstract : Nerve growth factor is required for the survival and maintenance of cholinergic neurons in the central nervous system. The direct infusion into the rat's septum of an anti-nerve growth factor monoclonal antibody, which inhibits nerve growth factor bioactivity seven times more strongly than a polyclonal antibody, caused very severe damage to the hippocampal cholinergic system. Anti-nerve growth factor polyclonal antibody also neutralized endogenously occurring nerve growth factor. The infusion of anti-nerve growth factor polyclonal antibody produced a dysfunction of memory and decreased choline acetyltransferase activity and acetylcholinesterase staining in the hippocampus. The cholinergic dysfunction and impairment of memory recovered to the normal level two weeks after cessation of the infusion of the anti-nerve growth factor polyclonal antibody. These results suggest that a deficit of nerve growth factor in the adult brain causes neuronal dysfunction.
ESTHER : Nitta_1993_Neurosci_57_495
PubMedSearch : Nitta_1993_Neurosci_57_495
PubMedID: 7508574

Title : Behavioral aspects of cholinergic transmission: role of basal forebrain cholinergic system in learning and memory -
Author(s) : Nabeshima T
Ref : Prog Brain Res , 98 :405 , 1993
PubMedID: 8248528

Title : Effects of NIK-247 on CO-induced impairment of passive avoidance in mice - Yoshida_1992_Eur.J.Pharmacol_214_247
Author(s) : Yoshida S , Nabeshima T , Kinbara K , Kameyama T
Ref : European Journal of Pharmacology , 214 :247 , 1992
Abstract : The effect of NIK-247 on carbon monoxide (CO)-induced amnesia were investigated. A step-down type passive avoidance task with mice was used to compare the effects of NIK-247 with those of tacrine. Two types of CO-induced amnesia model, acute and delayed models, were used. The acute amnesia model was developed using mice exposed to CO before memory consolidation, just after training, and a retention test carried out 24 h after training. The delayed amnesia model was prepared 7 days after CO exposure even when the animals were exposed to CO 4 h after training, after memory had consolidated. NIK-247 administered post-training at 0.03-0.3 and 3 mg/kg or pre-retention test (24 h after training) at 0.3 and 10 mg/kg attenuated the acute amnesia. In addition, NIK-247 (0.03, 0.1, 1 and 10 mg/kg) and tacrine (0.03, 0.1 and 1 mg/kg) administered before the retention test (7 days after CO exposure) improved retrieval in the delayed amnesia model. Tacrine (0.01-0.3 and 3 mg/kg), administered post-training, attenuated the acute amnesia but pre-retention test administration did not. The dose-response curves for NIK-247 and tacrine were biphasic bell-shaped. These results indicated that NIK-247 has an improving effect on hypoxia-induced acute and delayed cognitive dysfunction, and suggest that NIK-247 has promise as a nootropic drug for therapy of memory deficits in patients with cerebrovascular-type dementing disorders.
ESTHER : Yoshida_1992_Eur.J.Pharmacol_214_247
PubMedSearch : Yoshida_1992_Eur.J.Pharmacol_214_247
PubMedID: 1516640

Title : The effect of tacrine (THA) on cycloheximide- and basal forebrain lesion-induced memory deficit in rats - Nabeshima_1991_Jpn.J.Pharmacol_57_311
Author(s) : Nabeshima T , Maruyama E , Katoh A , Kameyama T
Ref : Japanese Journal of Pharmacology , 57 :311 , 1991
Abstract : The effects of 9-amino-1,2,3,4-tetrahydroacridine (tacrine), an active acetylcholinesterase inhibitor, on cycloheximide- and basal forebrain (BF) lesion-induced memory deficit in the water maze and passive avoidance task were investigated. While cycloheximide (1.5 mg/kg, s.c.) produced amnesia in the passive avoidance task, chronic administration of tacrine (1, 3 and 10 mg/kg, once a day for 1 week) improved the amnesia. BF lesion produced amnesia in both the water maze and passive avoidance tasks. Chronic tacrine (0.1-3 mg/kg, passive avoidance task, or 0.3 mg/kg, water maze task, once a day for 1 week) improved BF lesion-induced amnesia in the passive avoidance and water maze tasks. These results suggest that tacrine may be useful for senile dementia.
ESTHER : Nabeshima_1991_Jpn.J.Pharmacol_57_311
PubMedSearch : Nabeshima_1991_Jpn.J.Pharmacol_57_311
PubMedID: 1813659

Title : Utility of an elevated plus-maze for the evaluation of memory in mice: effects of nootropics, scopolamine and electroconvulsive shock - Itoh_1990_Psychopharmacology.(Berl)_101_27
Author(s) : Itoh J , Nabeshima T , Kameyama T
Ref : Psychopharmacology (Berl) , 101 :27 , 1990
Abstract : An elevated plus-maze consisting of two open and two enclosed arms was employed for an evaluation of memory in mice. Mice in the plus-maze escaped from the open arm to the enclosed arm because mice apparently dislike open and high spaces. The time it took for the mice to move from the open arm to the enclosed arm (transfer latency) was recorded. The transfer latency after the 2nd day was significantly shorter than that on the 1st day when it was recorded at a rate of one trial a day for 5 days. The transfer latency on the 2nd day was significantly prolonged in the mice administered electroconvulsive shock (300 V, 1 s) or scopolamine (20 micrograms, ICV) immediately after the first trial compared to the transfer latency in the control group. The prolongation of transfer latency in the mice administered an electroconvulsive shock was reversed by pretreatment with aniracetam (20 mg/kg, PO), but not tacrine and physostigmine. The prolongation of transfer latency in the mice administered scopolamine was reversed by pretreatment with aniracetam (10 and 20 mg/kg, PO) tacrine (1 and 3 mg/kg, PO), or physostigmine (0.025-0.2 mg/kg, IP). These results suggest that transfer latency may be one of the parameters of learning and memory.
ESTHER : Itoh_1990_Psychopharmacology.(Berl)_101_27
PubMedSearch : Itoh_1990_Psychopharmacology.(Berl)_101_27
PubMedID: 2343073

Title : Effects of the novel compound NIK-247 on impairment of passive avoidance response in mice - Nabeshima_1988_Eur.J.Pharmacol_154_263
Author(s) : Nabeshima T , Yoshida S , Kameyama T
Ref : European Journal of Pharmacology , 154 :263 , 1988
Abstract : The effects of NIK-247 [9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)-quinoline monohydrate hydrochloride] were studied on a model involving various types of drug- and electroconvulsive shock (ECS)-induced amnesia. The step-down type passive avoidance task in mice was used for comparison of the effects with those of tacrine, a 4-aminopyridine derivative which has an antiamnesic action. NIK-247 administered pre- and post-training or pre-retention test (24 h after training) prevented the disruption of memory induced by cycloheximide administered immediately after training. In addition, NIK-247 protected from the amnesia induced by treatment with ECS, phencyclidine and picrotoxin immediately after training. Tacrine failed to protect from ECS- and PCP-induced amnesia at the doses effective on cycloheximide-induced amnesia. The results indicate that NIK-247 improves cognitive functions at different phases of the learning and memory processes such as acquisition, consolidation, and retrieval in drug- and ECS-induced amnesia. NIK-247 may produce its antiamnesic effects via the cholinergic and GABAergic neuronal systems.
ESTHER : Nabeshima_1988_Eur.J.Pharmacol_154_263
PubMedSearch : Nabeshima_1988_Eur.J.Pharmacol_154_263
PubMedID: 3234481