| 16797712 |
Berry EV, Toms NJ: Pyruvate and oxaloacetate limit zinc-induced oxidative HT-22 neuronal cell injury. Neurotoxicology. 2006 Dec;27(6):1043-51. Epub 2006 May 22.
During CNS ischaemia, accumulating evidence suggests that raised intracellular Zn (2+) levels may play a significant role in inducing neuronal cell death. Several mechanisms mediating Zn (2+)-induced cell death have been suggested, however the precise molecular mechanisms remain uncertain. Employing the HT-22 murine hippocampal neuronal cell line, we have evaluated possible mechanisms of cytotoxic extracellular Zn (2+) insults. Increased extracellular Zn (2+) levels was found to induce concentration-dependent cytotoxicity. When tested at 200muM, Zn (2+) increased intracellular Zn (2+) levels (determined via FluoZin-3 fluorescence) and rapidly induced cell death. However, neither L-type (nimodipine) nor T-type (mibefradil) voltage-activated Ca (2+) channel inhibitors limited Zn (2+)-induced cytotoxicity. Furthermore, and in contrast with staurosporine, Zn (2+) cytotoxic insults failed to induce significant caspase-3 activation and were insensitive to the poly-caspase inhibitor, zVAD-fmk. Antioxidant co-application (Trolox and N,N'-diphenyl-1,4-phenylenediamine (DPPD)) was neuroprotective versus 6h Zn (2+) insults. Additionally, despite inducing significant mitochondrial membrane potential loss, Zn (2+) failed to induce detectable increased superoxide production. However, both pyruvate and oxaloacetate were found to afford significant neuroprotection versus Zn (2+) cytotoxic insults, without significantly influencing intracellular Zn (2+) accumulation. We conclude that cultured HT-22 neurones are vulnerable to Zn (2+) cytotoxic insults via a non-caspase-3 mediated mechanism, which involves glycolytic inhibition. |
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