Pro-GLP-1, a Pro-drug of GLP-1, is neuroprotective in cerebral ischemia

• Pro-GLP-1 is a long-lasting GLP-1 receptor agonist developed using a polymeric pro-drug strategy.
• Pro-GLP-1 conferred neuroprotective efficiency against cerebral in vitro and in vivo.
• Pro-GLP-1 stimulated the downstream of GLP-1 receptor signaling pathways.
• Pro-GLP-1 mediated anti-apoptotic effect after 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 7 days before middle cerebral artery occlusion (MCAO) surgery. The neurological deficit score and TTC staining were determined 24 h 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 12 h 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 PI3 K/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.

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