title: Pro-GLP-1, a Pro-drug of GLP-1, is neuroprotective in cerebral ischemia.
abstract: 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.
authors: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
authors: Huinan
authors: H
authors: Zhang
authors: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
authors: Jingru
authors: J
authors: Meng
authors: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
authors: Xubo
authors: X
authors: Li
authors: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
authors: Shimeng
authors: S
authors: Zhou
authors: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
authors: Di
authors: D
authors: Qu
authors: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
authors: Ning
authors: N
authors: Wang
authors: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
authors: Min
authors: M
authors: Jia
authors: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
authors: Xue
authors: X
authors: Ma
authors: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, China. Electronic address: xxluo3@fmmu.edu.cn.
authors: Xiaoxing
authors: X
authors: Luo
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage*; D057967:Infusions, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011355:Prodrugs / Q000008:administration & dosage*; D034741:RNA, Small Interfering / Q000008:administration & dosage
chemical_list: D018696:Neuroprotective Agents; D011355:Prodrugs; D034741:RNA, Small Interfering; D052216:Glucagon-Like Peptide 1
keywords: Cerebral ischemia; MCAO; Neuroprotective effect; Pro-GLP-1