Enhamcement of immobility in a forced swimming test by subacute or repeated treatment with phencyclidine : a new model of schizophrenia

Nabeshima.toshitaka 강원대학교 종합약학연구소 1999 약학연구 Vol.11 No.-

Involvement of Genetic and Environmental Factors in the Onset of Depression

Toshitaka Nabeshima,김형춘 한국뇌신경과학회 2013 Experimental Neurobiology Vol.22 No.4

First, this article provides a brief overview of the previous hypotheses regarding depression and then focuses on involvement ofgenetic and environmental factors in development of depression. According to epidemiological research, 30~40% of occurrences ofbipolar disorder involve a genetic factor. Therefore, environmental factors play a more important role in development of depression. Resilience and resistance to stress are common; therefore, although a certain extent of stress might be received during the embryonicor perinatal period, having a genetic predisposition to mental disorders does not imply that a mental disorder will develop. However,having a genetic predisposition to disorders does weaken resistance to stresses received during puberty, and without the ability torecover, a mental disorder is triggered. The importance of epigenetics in maintaining normal development and biology is reflected bythe observation that development of many diseases occurs when the wrong type of epigenetic marks are introduced or are added atthe wrong time or in the wrong place. Involvement of genetic and environmental factors in the onset of depression was investigatedin relation to epigenetics. When mice with the disrupted in schizophrenia 1 (DISC1) abnormal gene received isolated rearing stress,depression-like abnormal behaviors and decreased gene expression of tyrosine hydroxylase in the frontal cortex by epigeneticalsuppression via DNA methylation were observed. Decrease of dopamine in the frontal cortex triggers behavioral disorders. Administration of a glucocorticoid receptor antagonist resulted in full recovery from neurological and behavioral disorders. Theseresults suggest a new therapeutic approach to depression.

Molecular Mechanism of Drug Dependence: A role of tissue plasminogen activator in drug dependence

( Toshitaka Nabeshima ),( Taku Nagai ),( Kiyofumi Yamada ) 한국응용약물학회 2004 학술대회 Vol.2004 No.2

Animal models of Alzheimer's disease and evaluation of anti-dementia drugs

Yamada, Kiyofumi,Nabeshima, Toshitaka 한림대학교 환경·생명과학연구소 2002 [일송 국제심포지엄] 노화와 만성퇴행성 신경질환 Vol.- No.4

Alzheimer's disease(AD) is the most common cause of progressive decline of cognitive function in aged humans, and is characterized by the presence of numerous senile plaques and neurofibrillary tangles accompanied by neuronal loss. Some, but not all, of the neuropathological alterations and cognitive impairment in AD can be reproduced genetically and pharmacologically in animals. It should be possible to discover novel drugs that slow the progress or alleviate the clinical symptoms of AD by using these animal models. We review the recent progress in the development of animal models of AD and discuss how to use these model animals to evaluate novel anti-dementia drugs.

Molecular Mechanism of Cholinergic Dysfunction and Cognitive Deficits Induced by Amyloid β-Peptide

TRAN, Manh IIung,YAMADA, Kiyofumi,NABESHIMA, Toshitaka 한림대학교 환경·생명과학연구소 2002 [일송 국제심포지엄] 노화와 만성퇴행성 신경질환 Vol.- No.4

Amyloid β-peptide (Aβ) plays a critical role in the development of Alzheimer's disease(AD). Much progress has been made in understanding this age-related neurodegenerative disorder ; thus an insight into the cellular actions of Aβ and resulting functional consequences may contribute to preventive and therapeutic approaches for AD. In this review, recent evidence of Aβ-induced brain dysfunction, especially cholinergic impairment and memory deficits, is summarized. Moreover, proposed mechanisms for Aβ-induced neurotoxicity such as oxidative stress, ion-channel formation, and Aβ-receptor interaction are discussed.

Growth Hormone-Releaser Diet Attenuates Cognitive Dysfunction in Klotho Mutant Mice via Insulin-Like Growth Factor-1 Receptor Activation in a Genetic Aging Model

박석주,정윤희,이정현,Duy-Khanh Dang,남윤성,정지훈,김용선,Toshitaka Nabeshima,신은주,김형춘 대한내분비학회 2014 Endocrinology and metabolism Vol.29 No.3

Background: It has been recognized that a defect in klotho gene expression accelerates the degeneration of multiple age-sensitive traits. Accumulating evidence indicates that aging is associated with declines in cognitive function and the activity of growth hormone (GH)/insulin-like growth factor-1 (IGF-1). Methods: In this study, we examined whether a GH-releaser diet could be effective in protecting against cognitive impairment in klotho mutant mice. Results: The GH-releaser diet significantly induced the expression of IGF-1 and IGF-1 receptors in the hippocampus of klotho mutant mice. Klotho mutant mice showed significant memory impairments as compared with wild-type mice. In addition, the klotho mutation significantly decreased the expression of cell survival/antiapoptotic factors, including phospho-Akt (p-Akt)/phospho-glycogen synthase kinase3β (p-GSK3β), phospho-extracellular signal-related kinase (p-ERK), and Bcl-2, but significantly increased those of cell death/proapoptotic factors, such as phospho-c-jun N-terminal kinase (p-JNK), Bax, and cleaved caspase-3 in the hippocampus. Treatment with GH-releaser diet significantly attenuated both decreases in the expression of cell survival/antiapoptotic factors and increases in the expression of cell death/proapoptotic factors in the hippocampus of klotho mutant mice. In addition, klotho mutation-induced oxidative stress was significantly attenuated by the GH-releaser diet. Consequently, a GH-releaser diet significantly improved memory function in the klotho mutant mice. GH-releaser diet-mediated actions were significantly reversed by JB-1, an IGF-1 receptor antagonist. Conclusion: The results suggest that a GH-releaser diet attenuates oxidative stress, proapoptotic changes and consequent dysfunction in klotho mutant mice by promoting IGF-1 expression and IGF-1 receptor activation.

Mountain-Cultivated Ginseng Attenuates Phencyclidine-Induced Abnormal Behaviors in Mice by Positive Modulation of Glutathione in the Prefrontal Cortex of Mice

The-Vinh Tran,신은주,고성권,남윤성,정윤희,정지훈,장춘곤,나성열,Kiyofumi Yamada,Toshitaka Nabeshima,변재경,김형춘 한국식품영양과학회 2016 Journal of medicinal food Vol.19 No.10

Escalating evidence indicates that ginseng treatment protects against psychotoxic behaviors and memory impairment. Although the underlying mechanism of schizophrenia remains elusive, recent investigations proposed that downregulation of glutathione (GSH) can be involved in the pathogenesis of this disorder. Since little is known about the effects of ginseng in a schizophrenia-like animal model, we selected mountain-cultivated ginseng (MG) from a variety of ginseng extracts to investigate the effect of ginseng on the psychosis induced by phencyclidine (PCP) in mice. PCP (10 mg/kg/day, s.c.) was administered for 14 consecutive days. Novel object recognition, forced swimming, and social interaction tests were performed during the withdrawal period of 7 days. In addition, behavioral sensitization to an acute challenge of PCP was evaluated. The parameters of the GSH-dependent system in the prefrontal cortex (PFC) were examined. MG (200 mg/kg, i.p./day) or antipsychotic clozapine (10 mg/kg, p.o./day) was administered for seven consecutive days after the final PCP treatment. PCP significantly produced abnormal behaviors, followed by increases in Nrf2 nuclear translocation, its DNA binding activity, and glutamate–cysteine ligase (GCL) mRNA expression in the PFC. PCP treatment significantly decreased GSH/glutathione disulfide (GSSG) ratio and glutathione peroxidase (GPx) activity. MG significantly attenuated abnormal behaviors and the decreases in GSH/GSSG ratio and GPx activity induced by PCP. MG attenuated the increases in Nrf2 activity and GCL expression caused by PCP. The protective potentials of MG were comparable to those of clozapine. MG ameliorates PCP-induced schizophrenia-like psychosis in mice through the positive modulation of the glutathione system.

Comparison of the Effects of a Brand-name Drug and Its Generic Drug on the Quality of Life of Alzheimer’s Disease Patients

Mikio Sakakibara,Mitsuhiko Kido,Jun Kuribayashi,Hiroshi Okada,Ataru Igarashi,Hiroyuki Kamei,Toshitaka Nabeshima 대한정신약물학회 2015 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.13 No.2

Objective: The pharmacological effects of generic (GE) donepezil are the same as Aricept, its brand-name counterpart. However, little is known as to whether these two drugs provide the same quality of life (QOL). The study subjects were patients with Alzheimer’s disease who were taking donepezil hydrochloride tablets, and were selected by visiting either the local pharmacies or the patients’ homes. We chose the brand-name drug Aricept and its GE form donepezil to investigate, from a long-term caregiver’s perspective, the influence of both drugs on the patients’ QOL. Methods: An EuroQol-5 Dimension (EQ-5D) was used to assess the QOL of patients with Alzheimer’s disease, before and after various Aricept and/or donepezil regimens. Patients were divided into four groups: first time users of Aricept (n=43), first time users of GE donepezil (n=45), users refilling previous prescriptions of Aricept (n=51), and users switching from Aricept to GE donepezil (n=51). Results: The average change in the EQ-5D utility indices rose significantly in the patients starting a new regimen of Aricept and its GE drug. The patients continuing an existing regimen of Aricept showed no significant differences, even after Aricept was switched to a GE drug. Conclusion: The QOL of patients starting a new regimen of Aricept and its GE drug improved. The QOL was maintained upon switching to the GE drug form.

Role of microsomal epoxide hydrolase in methamphetamine-induced drug dependence in mice

Shin, Eun-Joo,Bing, Guoying,Chae, Jong Seok,Kim, Tae Woo,Bach, Jae-Hyung,Park, Dae Hun,Yamada, Kiyofumi,Nabeshima, Toshitaka,Kim, Hyoung-Chun Wiley Subscription Services, Inc., A Wiley Company 2009 Journal of neuroscience research Vol.87 No.16

<P>Microsomal epoxide hydrolase (mEH) and cytochrome P-450 (CYP) ensure the rapid detoxification of epoxides generated during the oxidative metabolism of xenobiotics. Although CYP has been demonstrated to modulate methamphetamine (METH)-induced behavioral effects, little is known about the role of the mEH gene on these effects. We examined the role of mEH gene expression in METH-induced conditioned place preference and behavioral sensitization by using mEH<SUP>–/–</SUP> and wild-type (WT) mice. Extracellular dopamine (DA) levels and DA uptake into synaptosomes were assessed by using an in vivo microdialysis and [<SUP>3</SUP>H]DA uptake assay. We applied double-label immunocytochemistry to characterize mEH-positive cellular types. METH-induced behavioral responses paralleled striatal c-Fos-like immunoreactivity. METH treatment resulted in increased extracellular DA levels in the nucleus accumbens but decreased synaptosomal DA uptake in the striatum. These behavioral and neurochemical changes were more pronounced in the mEH<SUP>–/–</SUP> mice than in WT mice. In WT mice, mEH-like immunoreactivity was expressed in astrocytes labeled by GFAP or S100B after METH treatment. The results suggest that epoxide intermediates mediate METH drug dependence and that astrocytic reactions of mEH protein are important in the endogenous modulation in response to METH drug dependence. © 2009 Wiley-Liss, Inc.</P>

Current understanding of methamphetamine-associated dopaminergic neurodegeneration and psychotoxic behaviors

신은주,Duy-Khanh Dang,The-Vinh Tran,Hai-Quyen Tran,정지훈,나승열,장춘곤,Kiyofumi Yamada,Toshitaka Nabeshima,김형천 대한약학회 2017 Archives of Pharmacal Research Vol.40 No.4

Clinical and preclinical studies have indicatedthat chronic methamphetamine (MA) use is associated withextensive neurodegeneration, psychosis, and cognitiveimpairment. Evidence from animal models has suggested aconsiderable role of excess dopamine or glutamate,oxidative stress, neuroinflammation, and apoptosis in MAinducedneurotoxicity, and that protein kinase Cd mightmediate the interaction among these factors. In addition,the relatively long-lasting and recurrent nature of MApsychosis has been reproduced in animals treated withvarious dosing regimens of MA, which have shownbehavioral sensitization, sociability deficits, and impairedprepulse inhibition. Genetic predisposition as well asdopaminergic and glutamatergic alterations might beimportant in the development of MA psychosis. Neuroimagingstudies have identified functional andmorphological changes related to the cognitive dysfunctionshown in chronic MA users. Failure in the task-evokedphosphorylation of extracellular signal-related kinaselikely underlies MA-induced memory impairment. Recentprogress has suggested certain roles of oxidative stress andneuroinflammation in the psychosis and cognitive deficitsinduced by repeated low doses of MA. This review providesa comprehensive description of pertinent findingsfrom human and animal studies, with an emphasis on thecurrent understanding of the underlying mechanisms ofMA neuropsychotoxicity and its relevance to Parkinson’sdisease or schizophrenia.