Patients with diabetes suffer more severe ischemic stroke. A combination of metformin and dipeptidyl peptide-4 inhibitors is commonly prescribed to treat diabetes. Therefore, we aimed to determine if pretreatment with a combination of metformin and evogliptin, a dipeptidyl peptidase-4 inhibitor, could reduce cerebral infarct volume in rats with streptozotocin-induced diabetes. After confirming diabetes induction, the rats were treated with vehicle, evogliptin, metformin, or evogliptin/metformin combination for 30 days. Then, stroke was induced by transient middle cerebral artery occlusion (tMCAO). Infarct volume, oxidative stress, levels of methylglyoxal-modified protein, glucagon-like peptide-1 receptor (GLP-1R), AMPK, and Akt/PI3K pathway-related proteins, and post-stroke pancreatic islet cell volume were evaluated. Compared to vehicle, only the co-administration group had significantly reduced infarct volume from the effects of tMCAO; the regimen also improved glycemic control, whereas the individual treatments did not. Co-administration also significantly reduced methylglyoxal-modified protein level in the core of the brain cortex, and the expression of 4-HNE and 8-OHdG was reduced. Co-administration increased p-Akt levels in the ischemic core and mitigated the suppression of Bcl-2 expression. Plasma GLP-1 and dipeptidyl peptidase-4 levels and brain GLP-1R expression remained unaltered. In the pancreas, islet cell damage was reduced by co-administration. These results reveal that metformin and evogliptin co-administration ameliorates cerebral infarction associated with prolonged glycemic control and pancreatic beta cell sparing. Other potential protective mechanisms may be upregulation of insulin receptor signaling or reduction of methylglyoxal-induced neurotoxicity. The combination of metformin and evogliptin should be tested further for its potential against focal cerebral ischemia in diabetes patients.
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