Delayed Mitochondrial Membrane Potential Disruption by ATP in Cultured Rat Hippocampal Neurons Exposed to N-Methyl-d-Aspartate

• Main Authors: Koichi Fujikawa, Noritaka Nakamichi, Shunsuke Kato, Ryo Fukumori, Miho Hida, Takeshi Takarada, Yukio Yoneda
• Format: Article
• Language: English
• Published: Elsevier 2012-01-01
• Series: Journal of Pharmacological Sciences
• Online Access: http://www.sciencedirect.com/science/article/pii/S1347861319305201

Necrotic damage leads to a massive leakage from injured cells of different intracellular constituents such as glutamate (Glu) and ATP, which are believed to play a role in the neuronal survival in the brain. In this study, we evaluated pharmacological properties of ATP, which is shown to be an endogenous inhibitor of N-methyl-d-aspartate (NMDA) receptors, on the neurotoxicity relevant to mitochondrial membrane potential disruption in cultured rat hippocampal neurons. Exposure to Glu or NMDA significantly inhibited cellular viability determined 24 and 48 h later, while simultaneous addition of 1 mM ATP significantly ameliorated the decreased viability in neurons exposed to Glu and NMDA, but not in those exposed to other cytotoxins. Both Glu and NMDA markedly increased intracellular free Ca2+ levels in a manner sensitive to blockade by the exposure to ATP, but not by that to adenosine. Exposure to ATP significantly delayed the rate of mitochondrial membrane potential disruption induced by Glu and NMDA. These results suggest that extracellular ATP would play a role as an endogenous antagonist endowed to protect rat hippocampal neurons from the excitotoxicity mediated by NMDA receptors in association with the delayed mitochondrial membrane potential disruption after the liberation from adjacent cells under necrotic death.[Supplementary materials: available only at http://dx.doi.org/10.1254/jphs.12034FP] Keywords:: glutamate, neurotoxicity, ATP, mitochondria, hippocampus