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Ischemic stroke is a major cause of neurological damage and brain dysfunction with consequent strong cerebral oxidative imbalance, inflammatory and apoptotic responses. Lixisenatide is a new potent glucagon-like peptide −1 (GLP-1) analogue that has been used clinically in the treatment of type II diabetes. Recent studies suggested the beneficial central effects of GLP-1-based therapies on different neurodegenerative diseases. This study aimed to investigate the ameliorative effect of lixisenatide in global cerebral ischemia-reperfusion (I/R) rat model and elaborate the underline mechanisms that could mediate the proposed activity. Adult male Wistar rats were subjected to sham operation or global cerebral I/R injury. Rats were administered the following drugs in two scheduled doses at 1 h and 24 h after reperfusion: lixisenatide (1 and 10 nmole/kg), lixisenatide plus GLP-1 receptor (GLP-1R) antagonist (exendin(9−39)), and pentoxiphylline.Comparable to pentoxiphylline; both doses of lixisenatide produced a significant reduction in infarct volume and amelioration of neurobehavioural functions along with suppression of oxidative stress parameters (catalase, reduced glutathione, malondialdehyde and NO), inflammatory marker (tumor necrosis factor-alpha) and apoptotic marker (caspase-3) in ischemic rat brains. However, these effects weren’tinhibited by GLP-1R antagonist, exendin(9−39), indicating that they are independent on GLP-1R mediation. Also, lixisenatide upregulated protein expression of cerebral endothelial nitric oxide synthase and the angiogenic marker, vascular endothelial growth factor. It's worth noting that this effect was blocked by exendin(9−39). Overall, these data indicated that lixisenatide may offer a promising approach for alleviating cerebral I/R injury via different mechanisms that could be mediated, in part, through GLP-1R.