title: Protection provided by cyclosporin A against excitotoxic neuronal death is genotype dependent.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Cell and Neurobiology, University of Southern California Keck School of Medicine, Los Angeles, California 90089-9112, USA.
authors.forename: Julia Belen
authors.initials: JB
authors.lastname: Santos
authors.forename: Paula Elyse
authors.initials: PE
authors.lastname: Schauwecker
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects* / Q000235:genetics; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D004827:Epilepsy / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D005838:Genotype; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007473:Ion Channels / Q000037:antagonists & inhibitors; D007608:Kainic Acid; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010641:Phenotype; D011292:Premedication; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018696:Neuroprotective Agents; D016572:Cyclosporine; D007608:Kainic Acid; D016559:Tacrolimus