Cyclosporin A and Bcl-2 do not inhibit quinolinic acid-induced striatal excitotoxicity in rodents.
Mitochondrial permeability transition (MPT) is a nonselective inner membrane permeabilization that contributes to neuronal cell death under circumstances such as brain trauma, ischemia, and hypoglycemia. Here we study the participation of MPT and the Bcl-2-sensitive apoptotic cell death pathway in glutamate receptor-mediated excitotoxicity. Intrastriatal infusions of the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid caused massive striatal neurodegeneration in both rats and mice. Interestingly, transgenic mice overexpressing human Bcl-2 and rats systemically treated with cyclosporin A did not exhibit reduced sensitivity to quinolinic acid-induced striatal toxicity. Both Bcl-2 and cyclosporin A are inhibitors of MPT; in addition Bcl-2 also inhibits apoptotic stimuli-mediated release of mitochondrial apoptogenic factors. Isolated brain mitochondria from cyclosporin A-treated rats showed resistance to Ca(2+)-induced dissipation of the membrane potential, indicating protection against MPT. We conclude that quinolinic acid-mediated striatal excitotoxicity is not dependent on MPT and Bcl-2-sensitive apoptotic cell death pathways.
Maciel
Evelise N
EN
Departamento de Patologia Clinica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, 13083-970, Campinas, SP, Brazil.
Kaminski Schierle
Gabriele S
GS
Hansson
Oskar
O
Brundin
Patrik
P
Castilho
Roger F
RF
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001923:Brain Chemistry; D002118:Calcium / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D017378:Quinolinic Acid / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D009498:Neurotoxins; D019253:Proto-Oncogene Proteins c-bcl-2; D000244:Adenosine Diphosphate; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D017378:Quinolinic Acid; D002118:Calcium