Brief low Mg2+o-induced Ca2+ spikes inhibit subsequent prolonged exposure-induced excitotoxicity in cultured rat hippocampal neurons.
10.4196/kjpp.2016.20.1.101
- Author:
Hee Jung KIM
1
;
Ji Seon YANG
;
Shin Hee YOON
Author Information
1. Department of Physiology, College of Medicine, Dankook University, Cheonan 31116, Korea.
- Publication Type:Original Article
- Keywords:
Ca2+ spikes;
Excitotoxicity;
Low [Mg2+]o preconditioning
- MeSH:
Animals;
Calcium-Calmodulin-Dependent Protein Kinase Type 2;
Cell Death;
Cycloheximide;
N-Methylaspartate;
Neurons*;
Nimodipine;
Phosphatidylinositol 3-Kinases;
Phosphotransferases;
Rats*;
Receptors, AMPA;
Seizures
- From:The Korean Journal of Physiology and Pharmacology
2016;20(1):101-109
- CountryRepublic of Korea
- Language:English
-
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 Go6976, a specific inhibitor of PKCalpha had no effect on the tolerance, both the PKCepsilon translocation inhibitor and the PKCzeta 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 PKCepsilon and PKCxi, JAK-2, MAPK kinase, CaMKII and the de novo synthesis of proteins.
