title: Activation of cell death pathway after a brief period of global ischemia in diabetic and non-diabetic animals.
abstract: Mitochondria play a critical role in the pathogenesis of cerebral ischemia. Acute hyperglycemia has been shown to activate the mitochondria-initiated cell death pathway after an intermediate period of ischemia. The objective of the present study was to determine if diabetic hyperglycemia induced by streptozotocin activates the cell death pathway after a brief period of global ischemia. Five minutes of global ischemia was induced in nondiabetic and diabetic rats. Brain samples were collected after 30 min, 6 h, 1, 3, and 7 days of recirculation as well as from sham-operated controls. Histopathological examination in the hippocampal CA1, CA3, hilus, and dentate gyrus regions, as well as in the cortical and thalamic areas, showed that neuronal death in diabetic animals increased compared to nondiabetic ischemic controls. Neuronal damage maturation occurred after 7 days of recovery in nondiabetic rats, while it was shortened to 3 days of recovery in diabetic animals. Western blot analyses revealed that release of cytochrome c markedly increased after 1 and 3 days of reperfusion in diabetic rats. Caspase-3 activation was evident in the nuclear fraction of the cortex of diabetic rats after 3 days recovery and it was preceded by activation of caspase-9, but not activation of caspase-8. Electron microscopy demonstrated that chromatin condensation and mitochondrial swelling were features of the diabetes-mediated ischemic neuronal damage. However, no apoptotic bodies were observed in any sections examined. These results suggest that a brief period of global ischemia in diabetic animals activates a neuronal cell death pathway involving cytochrome c release, caspase-9 activation, and caspase-3 cleavage, all of which are most likely initiated by early mitochondria damage.
authors.affiliation: Cardiovascular Research Center and Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu 96822, USA.
authors.forename: Chaonan
authors.initials: C
authors.lastname: Ding
authors.forename: QingPing
authors.initials: Q
authors.lastname: He
authors.forename: Ping-An
authors.initials: PA
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000473:pathology / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000473:pathology / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013311:Streptozocin; D013788:Thalamus / Q000378:metabolism* / Q000473:pathology
chemical_list: D013311:Streptozocin; D020169:Caspases