Brief low [Mg2+]o-induced Ca2+ spikes inhibit subsequent prolonged exposure-induced excitotoxicity in cultured rat hippocampal neurons |
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Authors: | Hee Jung Kim Ji Seon Yang Shin Hee Yoon |
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Institution: | 1Department of Physiology, College of Medicine, Dankook University, Cheonan 31116, Korea.;2Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.;3Catholic Neuroscience Institute, The Catholic University of Korea, Seoul 06591, Korea. |
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Abstract: | Reducing Mg2+]o to 0.1 mM can evoke repetitive Ca2+]i spikes and seizure activity, which induces neuronal cell death in a process called excitotoxicity. We examined the issue of whether cultured rat hippocampal neurons preconditioned by a brief exposure to 0.1 mM Mg2+]o are rendered resistant to excitotoxicity induced by a subsequent prolonged exposure and whether Ca2+ spikes are involved in this process. Preconditioning by an exposure to 0.1 mM Mg2+]o for 5 min inhibited significantly subsequent 24 h exposure-induced cell death 24 h later (tolerance). Such tolerance was prevented by both the NMDA receptor antagonist D-AP5 and the L-type Ca2+ channel antagonist nimodipine, which blocked 0.1 mM Mg2+]o-induced Ca2+]i spikes. The AMPA receptor antagonist NBQX significantly inhibited both the tolerance and the Ca2+]i spikes. The intracellular Ca2+ chelator BAPTA-AM significantly prevented the tolerance. The nonspecific PKC inhibitor staurosporin inhibited the tolerance without affecting the Ca2+]i spikes. While Gö6976, a specific inhibitor of PKCα had no effect on the tolerance, both the PKCε translocation inhibitor and the PKCζ pseudosubstrate inhibitor significantly inhibited the tolerance without affecting the Ca2+]i spikes. Furthermore, JAK-2 inhibitor AG490, MAPK kinase inhibitor PD98059, and CaMKII inhibitor KN-62 inhibited the tolerance, but PI-3 kinase inhibitor LY294,002 did not. The protein synthesis inhibitor cycloheximide significantly inhibited the tolerance. Collectively, these results suggest that low Mg2+]o preconditioning induced excitotoxic tolerance was directly or indirectly mediated through the Ca2+]i spike-induced activation of PKCε and PKCξ, JAK-2, MAPK kinase, CaMKII and the de novo synthesis of proteins. |
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Keywords: | Ca2+ spikes Excitotoxicity Low [Mg2+]o preconditioning |
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