Pro-GLP-1, a Pro-drug of GLP-1, is neuroprotective in cerebral ischemia. 
Pro-Glucagon-like peptide-1 (Pro-GLP-1), a long-lasting GLP-1 receptor (GLP-1R) agonist, was developed using a polymeric pro-drug strategy and its neuroprotective effects on ischemic stroke were investigated in C57BL/6 mice.  Pro-GLP-1 was injected into the intraperitoneal cavity of C57BL/6 mice once a day for 7days before middle cerebral artery occlusion (MCAO) surgery.  The neurological deficit score and TTC staining were determined 24h after ischemia.  The results demonstrated that Pro-GLP-1 was slowly degraded in the plasma and brain of the mice, and GLP-1 could be detected even 12h after administration.  Pro-GLP-1 was significantly neuroprotective in C57BL/6 mice subjected to MCAO.  In cultured cortical neurons, treatment with Pro-GLP-1 attenuated apoptosis induced by oxygen-glucose deprivation (OGD).  The neuroprotective effects of Pro-GLP-1 were blocked by a selective GLP-1 receptor antagonist and knockdown of GLP-1 receptor with shRNA.  However, Pro-GLP-1 had no effect on blood glucose and insulin levels which indicated that neuroprotection was mediated by the activation of GLP-1 receptor in the brain.  Pro-GLP-1 repaired the balance of pro- and anti-apoptotic proteins and decreased the expression of caspase-3.  The anti-apoptotic effect was mediated by the cAMP/PKA and PI3K/Akt pathway.  Our research provides evidence that pre-treatment of MCAO mice with Pro-GLP-1 exerts a neuroprotective effect mediated by a blockade of apoptosis and that Pro-GLP-1 might be a potential neuroprotective agent candidate against ischemic stroke.