Early release of cytochrome C and activation of caspase-3 in hyperglycemic rats subjected to transient forebrain ischemia.
The mechanisms underlying the aggravating effect of hyperglycemia on brain damage are still elusive. The present study was designed to test our hypothesis that hyperglycemia-mediated damage is caused by mitochondrial dysfunction with mitochondrial release of cytochrome c (cyt c) to the cytoplasm, which leads to activation of caspase-3, the executioner of cell death. We induced 15 min of forebrain ischemia, followed by 0.5, 1, and 3 h of recirculation in sham, normoglycemic and hyperglycemic rats. Release of cyt c was observed in the neocortex and CA3 in hyperglycemic rats after only 0.5 h of reperfusion, when no obvious neuronal damage was observed. The release of cyt c persisted after 1 and 3 h of reperfusion. Activation of caspase-3 was observed after 1 and 3 h of recovery in hyperglycemic animals. No cyt c release or caspase-3 activation was observed in sham-operated controls while a mild increase of cyt c was observed in normoglycemic ischemic animals after 1 and 3 h of reperfusion. The findings that there is caspase activation and cyt c relocation support a notion that the biochemical changes that constitute programmed cell death occur after ischemia and contribute, at least in part, to hyperglycemia-aggravated ischemic neuronal death.
The Queen's Medical Center, Center for the Study of Neurological Disease, 1356 Lusitana Street, UH Tower 813, Honolulu, HI 96813, USA. pingan@cns.queens.org
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D000818:Animals; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D003574:Cytochrome c Group / Q000032:analysis / Q000378:metabolism*; D006943:Hyperglycemia / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000201:enzymology; D009474:Neurons / Q000166:cytology / Q000201:enzymology; D016548:Prosencephalon / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D003574:Cytochrome c Group; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases