Exposure to
hyperglycemia after
cerebral ischemia exacerbates cerebral damage; however, little is known regarding the mechanism. In this study, we focused on the relationship between post-ischemic
hyperglycemia and mitochondrial homeostasis at the early stage of
ischemia (within the 6 h clinical therapeutic window for thrombolysis). Permanent
cerebral ischemia was induced by
middle cerebral artery occlusion (pMCAO) for 1, 3, and 6 h. We first elucidated the role of post-ischemic
hyperglycemia on mitochondria-mediated injury by testing
reactive oxygen species generation, cyt-c release, and
caspase-3 activation. Next, we analyzed mitochondrial homeostasis by testing the
protein levels related to fission, fusion, biogenesis and elimination. The results showed that
hyperglycemia further augmented the mitochondria-mediated injury induced by pMCAO. No significant differences of Fis1, Opa1 and Mfn2 were observed at each time point. There is no significant influence on these three
proteins after
hyperglycemia in rats of the experimental group compared to their counterparts in the control group. The translocation of the fission
protein Drp1 to the mitochondrial outer-membrane increased at 1 h after pMCAO and later steadily decreased over time in normal animals. However,
hyperglycemia inhibited both the levels of Drp1 in the cytoplasm and mitochondria. Moreover,
hyperglycemia inhibited mitophagy induced by pMCAO at 1 h, although the overall autophagy was increased. In conclusion, pMCAO transiently induced the mitochondrial fission and their elimination by mitophagy. However,
hyperglycemia abolished this adaptation reaction of the mitochondria and thus resulted in the accumulation of damaged mitochondria and subsequent damage. Our findings help to refine our understanding of the role of post-ischemic
hyperglycemia in brain ischemic injury.