期刊
NEUROSCIENCE LETTERS
卷 469, 期 3, 页码 303-308出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2009.12.013
关键词
SA4503; MAPK; ERK; AMPA; Antidepressant; Cell death
资金
- Heiwa Nakajima Foundation
- Ichiro, Kanehara Foundation
- Japan Health Sciences Foundation
- Health and Labor Sciences Research Grants
- Mitsubishi Pharma Research Foundation
- Japan Foundation for Neuroscience and Mental Health
- National Institute of Biomedical Innovation
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [21680034]
- Grants-in-Aid for Scientific Research [21680034] Funding Source: KAKEN
Many studies suggest that antidepressants act as neuroprotective agents in the central nervous system (CNS), though the underlying mechanism has not been fully elucidated. In the present study, we examined the effect of SA4503. which is a sigma-1 receptor agonist and a novel antidepressant candidate, on oxidative stress-induced cell death in cultured cortical neurons. Exposure of the neurons to H2O2 induced cell death, while pretreatment with SA4503 inhibited neuronal cell death. The SA4503-dependent survival effect was reversed by co-application with BD1047 (an antagonist of sigma-1/2 receptors). Previously we found that H2O2 triggers a series of events including over-activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and intracellular Ca2+ accumulation via voltage-gated Ca2+ channels and ionotropic glutamate receptors, resulting in neuronal cell death (Numakawa et al. (2007) [20]). Importantly, we found in this study that SA4503 reduced the activation of the MAPK/ERK pathway and down-regulated the ionotropic glutamate receptor, GluR1. Taking these findings together, it is possible that SA4503 blocks neuronal cell death via repressing activation of the MAPK/ERK pathway and, consequently, expression levels of glutamate receptors. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
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