Pyruvate and oxaloacetate limit zinc-induced oxidative HT-22 neuronal cell injury.

EV Berry, NJ Toms

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)1043-1051
Number of pages0
JournalNeuroToxicology
Volume27
Issue number6
DOIs
Publication statusPublished - Dec 2006

Keywords

  • Analysis of Variance
  • Animals
  • Caspase 3
  • Cell Death
  • Cell Line
  • Transformed
  • Cytotoxins
  • Diagnostic Imaging
  • Dose-Response Relationship
  • Drug
  • Drug Interactions
  • Flow Cytometry
  • Insecticides
  • Membrane Potential
  • Mitochondrial
  • Mice
  • Neurons
  • Oxaloacetic Acid
  • Phenanthridines
  • Pyruvic Acid
  • Rotenone
  • Zinc

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