Liraglutide protects against diabetes mellitus complicated with focal cerebral ischemic injury by activating mitochondrial ATP-sensitive potassium channels

Abstract

Cerebral infarction is a common disease that threatens the health of humankind worldwide. Diabetes is one of the important causes of cerebral ischemic (CI) injury. CI complicated with diabetes has a worse prognosis and lacks effective treatment. Our preliminary study demonstrated that liraglutide mitigates CI injuries in diabetic rats. However, the essential mechanism underlying this effect remained to be fully investigated. Recent research has shown that damaged mitochondrial ATP-sensitive potassium channels (mitoKATP) play a critical role in diabetes-aggravated CI injury. Therefore, we hypothesized that liraglutide may confer therapeutic effects against CI with diabetes by activating mitoKATP channels. In this study, liraglutide, but not insulin, significantly improved ischemia-induced neurological deficits and decreased infarct volumes following CI in diabetic rats, down-regulated the expression of myeloperoxidase and up-regulated the expression of superoxide dismutase and two subunits of the mitoKATP channel (SUR1 and Kir6.2). However, these effects were weakened by the mitoKATP antagonist 5-hydroxydecanoic acid. Our study demonstrated that the neuroprotective effects of liraglutide on CI injury with diabetes, which occurs by reducing oxidative stress and the inflammatory response, are associated with the activation of the mitoKATP channel.