Protection provided by cyclosporin A against excitotoxic neuronal death is genotype dependent

Epilepsia. 2003 Aug;44(8):995-1002. doi: 10.1046/j.1528-1157.2003.66302.x.

Abstract

Purpose: Previous studies have shown that the immunosuppressant cyclosporin A (CsA), a specific blocker of the mitochondrial permeability transition (MPT) pore, can dramatically ameliorate the selective neuronal necrosis resulting from ischemia-reperfusion, traumatic brain injury, and N-methyl-d-aspartate (NMDA)-evoked neurotoxicity. The purpose of this study was to determine whether two different immunosuppressants, CsA and FK-506, could ameliorate the neuronal damage observed after kainate-induced seizures in strains that are differentially susceptible to excitotoxin-induced cell death.

Methods: Excitotoxin-resistant (C57BL/6) or -susceptible (FVB/N) mice were administered kainate alone (30 mg/kg), CsA alone (5, 10, or 20 mg/kg), or one of the immunosuppressants (CsA, 5 mg/kg or 10 mg/kg; FK-506, 0.5 mg/kg) followed by kainate. After drug administration, mice were monitored continuously for the onset and extent of seizure activity. After a survival of 7 days, animals were assessed for hippocampal damage.

Results: Whereas CsA alone induced no epileptogenic effects and both immunosuppressants were without effect on the induction of kainate-induced seizures, administration of CsA to excitotoxin-susceptible mice (FVB/N) virtually eliminated neuronal cell death. In contrast, induction of neuronal cell death was evident when CsA was administered to excitotoxin-resistant mice (C57BL/6). Administration of FK-506, another commonly used immunosuppressant, which lacks an effect on the MPT, had no effect on modification of susceptibility to kainate-induced cell death in either strain.

Conclusions: As our data show differential protection of hippocampal neurons against excitotoxic cell death by pretreatment with CsA, these results suggest that strain-dependent differences in mitochondrial integrity and function may exist.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Death / drug effects*
  • Cell Death / genetics
  • Cyclosporine / pharmacology*
  • Dose-Response Relationship, Drug
  • Electroencephalography / drug effects
  • Epilepsy / chemically induced
  • Epilepsy / genetics*
  • Epilepsy / pathology
  • Genotype*
  • Hippocampus / drug effects*
  • Hippocampus / pathology
  • Ion Channels / antagonists & inhibitors
  • Kainic Acid
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mitochondrial Membrane Transport Proteins
  • Neurons / drug effects
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Phenotype
  • Premedication
  • Tacrolimus / pharmacology

Substances

  • Ion Channels
  • Mitochondrial Membrane Transport Proteins
  • Neuroprotective Agents
  • mitochondrial permeability transition pore
  • Cyclosporine
  • Kainic Acid
  • Tacrolimus