Mechanisms of free radical formation and toxicity in an in vitro model of ischemia
Abstract (Summary)In light of recent observations suggesting that fiee radical (FR) formation is an obligatory step of excitotoxic neuronal death, the knowledge of the molecular rnechanisms by which FRs are produced and induce ce11 damage is very important. Results of this study suggest that ischemic FR generation occurs due to glutamate-mediated intracellular calcium rises primanly in rnitochondria and depends on mitochondriai calcium uptake and pyridine nucleotide hydrolysis. Also presented is the first direct evidence of ischemia-induced prolonged, Cyclosporin A-sensitive loss of mitochondrial potential- indicative of a specific mitochondrial dysfùnction, termed the mitochondrial penneability transition (WT). Isolation and identification of mitochondnal proteins on Cyclosporin A affinity column suggest that MPT rnight be accomplished by the assembly of a mitochondrial pore-forming protein, porin. cyclophiiins. and possibly other proteins. into a mitochondrial megachannel. In addition, reactive oxygen species and mitochondrial dystùnction are found to play a major role in ischemic neurodegeneration. as indicated by the high neuroprotective etficacy of agents preventinç FR formation and mitochondrial dystùnction. and free radical scavengers. In sumrnary. these data suggest that rnitochondria are the principal source and the primary target of ischernic oxidative stress. and therefore are a major determinant of the ceilular fate.
Source Type:Master's Thesis
Date of Publication:01/01/1999