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.
['Zhang|Huinan|H|', 'Meng|Jingru|J|', 'Li|Xubo|X|', 'Zhou|Shimeng|S|', 'Qu|Di|D|', 'Wang|Ning|N|', 'Jia|Min|M|', 'Ma|Xue|X|', 'Luo|Xiaoxing|X|']
D000818:Animals D002545:Brain Ischemia D002478:Cells, Cultured D004305:Dose-Response Relationship, Drug D052216:Glucagon-Like Peptide 1 D057967:Infusions, Intraventricular D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D009474:Neurons D018696:Neuroprotective Agents D011355:Prodrugs D034741:RNA, Small Interfering
Pro-GLP-1 Cerebral ischemia Neuroprotective effect MCAO