A dual GLP-1/GIP agonist inhibits oxidative stress in diabetic rats with cerebral ischemia-reperfusion injury by activating the Nrf2/ARE signaling pathway

Abstract

Stroke is the leading cause of disability-affected life years in China, posing a great social hazard. Diabetes is a chronic disease that seriously affects human health that can aggravate cerebral ischemia - reperfusion injury. Oxidative stress is the main mechanism through which hyperglycemia aggravates cerebral ischemia - reperfusion injury. Our aim is to investigate whether incretins (GLP-1 and GIP) can exert neuroprotective effects by activating the Nrf2/ARE pathway to reduce oxidative stress, and to compare the efficacy of the single GLP-1- receptor liraglutide and the dual GLP-1/GIP receptor agonist DA3-CH. Methods and Results: Male Sprague-Dawley rats were randomly divided into 4 groups and treated with STZ and with either saline, liraglutide or with DA3-CH (10mmol/kg, once-daily ip. for 14 days). Thereafter, rats underwent middle cerebral artery occlusion followed by 24-h reperfusion. The drugs reduced blood glucose levels, decreased the infarct area, and lowered the neurological deficit score. They furthermore mitigated oxidative stress damage, enhanced the ability of brain tissue to scavenge ROS, and increased the expression of proteins in the Nrf2/ARE signaling pathway, including Nrf2, HO-1, and NQO1.Conclusions: The drugs inhibit oxidative stress through activating the Nrf2/ARE pathway. Overall, DA3-CH was superior to liraglutide.