Impact of Diabetes on Oxidative Stress, Mitochondrial Function, and Neurological Outcomes Following Ischemic Stroke: A Sex-Based Experimental Analysis.

Diabetes mellitus (DM) contributes to vascular complications through inflammation, endothelial dysfunction, oxidative stress, and mitochondrial impairment. Ischemic stroke (IS) is a common complication of DM and a leading cause of long-term neurological disability. Although DM elevates the risk of IS, the underlying mechanisms affecting stroke outcomes remain unclear. Sex differences may also influence IS progression, but further research is needed. This study aimed to experimentally evaluate the impact of DM on IS outcomes and compare the acute outcomes in males and females through a screening of neurochemical, neurological parameters, and peripheral immune response. Male and female Wistar rats aged 60 days were induced to DM by alloxan administration and subsequently to IS by middle cerebral artery occlusion (MCAO). General health status and neurological deficits were evaluated in the animals at 1 and 24 h post-MCAO. At 24 h post-MCAO, samples were collected for analysis of serum and urinary glucose, weight and spleen dimensions, blood immune cells and corticosterone levels, ileum histology, brain receptor for advanced glycation end products (RAGE) expression, brain oxidative stress, and mitochondrial parameters. Alloxan induced DM, promoting hyperglycemia and glycosuria. MCAO resulted in greater weight loss in males. Males and females presented different post-MCAO responses in peripheral organs, with females exhibiting leukopenia, neutrophilia, and lymphocytosis. Males were more sensitive to serum corticosterone elevations and demonstrated greater acute RAGE activation. Males and females exhibited differential responses to oxidative stress, cytokines, and mitochondrial function. Males demonstrated greater myeloperoxidase (MPO) activity in the cerebellum, a greater quantity of carbonylated proteins in the hippocampus, lower basal superoxide dismutase activity in the cortex and cerebellum, and lower catalase activity in the hippocampus and striatum. Males also presented lower basal activity of complex I in the hippocampus and complex II-succinate dehydrogenase in the prefrontal cortex, cortex, and striatum. DM potentiated, in post-MCAO males, the reduction of IL-6 in the hippocampus and cortex, hippocampal MPO activity, reduced complex I activity in the prefrontal cortex and complex II-III in the hippocampus, hippocampal RAGE expression, and neurological deficits 24 h after ischemia. In females, DM potentiated prefrontal cortex MPO activity, elevated striatal nitrite/nitrate concentration, and reduced complex IV activity in the cortex. We demonstrated that DM significantly worsens brain damage caused by IS, especially in male rats. DM intensifies the effects of IS on oxidative stress, neuroinflammation, and mitochondrial function. The impact of DM extends beyond the brain, also affecting organs such as the spleen and intestine, and altering blood cells. Males are more vulnerable to damage and neurological deficits, while females exhibit different responses to IS when diabetic.