title: Protective effects of NMDA receptor antagonist, memantine, against senescence of PC12 cells: A possible role of nNOS and combined effects with donepezil.
abstract: Alzheimer disease (AD) is a neurodegenerative disorder characterized by cognitive dysfunction. The pathology of AD is mainly related to amyloid ß (Aß)-peptides, but glutamate-mediated toxicity is also one of the main processes of memory impairment in AD. Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS) and is particularly involved in synaptic plasticity, memory, and learning. Memantine is a low-affinity voltage-dependent noncompetitive antagonist at glutamatergic NMDA receptors. Here,we investigated whether memantine protects against glutamate-induced senescence. In PC12 cells, treatment with glutamate induced senescent phenotypes as judged by the cell appearance and senescence-associated ß-galactosidase (SA-ßgal) in parallel with decreased SIRT1 and increased p53 expression. However, treatment with memantine decreased glutamate-induced senescent PC12 cells and reversed the changes in SIRT1 and p53 expression. Glutamate is known to stimulate the production of NO and O2(-) and has the capacity to generate ONOO(-) in the CNS. Therefore, we investigated whether glutamate activates nNOS and memantine reverses it. Treatment with glutamate increased nNOS expression, activity, and production of NO,whereas memantine blocked them. Next, the in vivo effects of memantine on cognitive function in senescence-accelerated mouse prone 8 (SAMP8), as a model of AD, were investigated. In the Morris water maze test, SAMP8 showed a marked decline in performance, but memantine administration improved it. Moreover, neuronal senescence and the level of oxidative stress in the hippocampus were decreased by memantine. Finally, the effects of combination treatment with memantine and donepezil, a cholinesterase inhibitor, were investigated. We observed additive effects of memantine and donepezil on the senescent phenotype of PC12 cells and the hippocampus of SAMP8. These results indicate that inhibition of the NMDA receptor by memantine leads to a decrease innNOS activity and results in a reduction of glutamate-induced senescence. Thus, our present study suggests a critical role of memantine in the prevention of neuronal aging, and supports that donepezil has a combined effect with memantine.
authors.affiliation: Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Electronic address: hidetaka-ota@umin.ac.jp.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Ota
authors.affiliation: Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Sumito
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Federation of National Public Service Personnel Mutual Aid Associations, Toranomon Hospital, Minato-ku, Tokyo, Japan.
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Ouchi
authors.affiliation: Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Akishita
mesh_terms: D000375:Aging / Q000187:drug effects*; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D000077265:Donepezil; D018698:Glutamic Acid / Q000737:chemistry*; D006624:Hippocampus / Q000187:drug effects; D007189:Indans / Q000627:therapeutic use*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008559:Memantine / Q000627:therapeutic use*; D008568:Memory / Q000187:drug effects; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D016716:PC12 Cells; D010880:Piperidines / Q000627:therapeutic use*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D000077265:Donepezil; D052248:Nitric Oxide Synthase Type I; D001616:beta-Galactosidase; D008559:Memantine
keywords: Alzheimer disease; Cellular senescence; Donepezil; Memantine; Nitric oxide