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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.
Anti-dementia Activity of Nobiletin, a Citrus Flavonoid: A Review of Animal Studies
Akira Nakajima,Kiyofumi Yamada,Yasushi OHIZUMI 대한정신약물학회 2014 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.12 No.2
Alzheimer’s disease (AD), the most common form of dementia among the elderly, is characterized by the progressive declineof cognitive function and has a detrimental impact worldwide. Despite intensive laboratory and clinical research over the lastthree decades, pharmacological options for the prevention and effective long-term treatment of AD are not currently available. Consequently, successful therapeutic and preventive treatments for AD are needed. When researching materials from naturalresources having anti-dementia drug activity, we identified nobiletin, a polymethoxylated flavone from the peel of Citrus depressa. Nobiletin exhibited memory-improving effects in various animal models of dementia and exerted a wide range of beneficial effectsagainst pathological features of AD including amyloid-β (Aβ) pathology, tau hyperphosphorylation, oxidative stress, cholinergicneurodegeneration and dysfunction of synaptic plasticity-related signaling, suggesting this natural compound could become anovel drug for the treatment and prevention of AD.
Roles of Matrix Metalloproteinases and Their Targets in Epileptogenesis and Seizures
Hiroyuki Mizoguchi,Kiyofumi Yamada 대한정신약물학회 2013 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.11 No.2
Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) remodel the pericellular environment by regulating the cleavage of extracellular matrix proteins, cell surface components, neurotransmitter receptors, and growth factors,which together regulate cell adhesion, synaptogenesis, synaptic plasticity, and long-term potentiation. Increased MMP activity and dysregulation of the balance between MMPs and TIMPs have also been implicated in various pathological conditions. Recent studies have suggested that prolonged seizures are associated with high MMP levels in serum and neural tissues, and certain extracellular macromolecule targets may influence the pathogenesis of epilepsy and seizure. In this review, we discuss the roles of MMP activation in animal models of epilepsy
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.
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.
Shin, Eun-Joo,Jeong, Ji Hoon,Kim, Hyun Ji,Jang, Choon-Gon,Yamada, Kiyofumi,Nabeshima, Toshitaka,Kim, Hyoung-Chun The Japanese Pharmacological Society 2007 Journal of pharmacological sciences Vol.105 No.4
<P>We demonstrated that exposure to extremely low frequency magnetic fields (ELF-MF) enhanced dopamine levels in the rat striatum. To extend our understanding, we examined the role of dopaminergic receptors in ELF-MF–induced behavioral changes. Exposure to ELF-MF (2.4 mT, 1 h/day, for one or seven days) enhanced locomotor activity in a time-dependent manner. This hyperlocomotor activity paralleled an increase in c-Fos-like immunoreactivity (c-Fos-IR). Pretreatment with SCH23390, a dopaminergic D<SUB>1</SUB>-like receptor antagonist, but not with sulpiride, a dopaminergic D<SUB>2</SUB>-like receptor antagonist, inhibited ELF-MF–induced increased locomotor activity and c-Fos-IR. Thus, our results suggest that ELF-MF–induced behavioral responses are, at least in part, mediated by activation of dopamine D<SUB>1</SUB>-like receptors.</P>
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>