Influence of diabetes mellitus on cerebral ischemia and reperfusion injury

Diabetes mellitus aggrevates and worsens the brain damage caused by global or focal cerebral ischemia. The purpose of our study was to explore what is the underlying mechanism of the exaggerated brain damage caused by diabetic ischemia. In our experiments we investigated whether there is a difference in the activation of the mitochondria-dependent apoptotic pathway after ischemic injury in diabetic rats compared to non-diabetic animals. In further experiments we examined whether increased free radical production and activation of astrocytes contribute to the exaggerated brain damage after diabetic ischemia compared to non-diabetic ischemia. Finally, we investigated the heat shock protein expression and synthesis in hyperglycemic ischemia. Early activation of apoptotic cell death pathway in diabetic animals was observed. The results show that the production of free radicals such as superoxide anion, nitric oxide and peroxynitrite are stimulated in neurons after diabetic ischemic injury. In astrocytes only nitric oxide production was enhanced. These data suggest that diabetic ischemia increases peroxynitrite production in neurons by enhancing the formation of superoxide since peroxynitrite is derived from the reaction of NO and superoxide. As a reaction to the increased stress caused by hyperglycemia enhanced the heat shock protein expression and synthesis in neuronal cells. Finally, we detected reactive astrogliosis in both ischemic groups, although in the diabetic animals damage of astrocytes was observed early after the ischemic injury. These results draw attention to the enhanced intracellular events leading to cell damage may further limit the time-window of the effective therapy, if the patient suffer from diabetes mellitus.