Pro-GLP-1, a Pro-drug of GLP-1, is neuroprotective in cerebral ischemia
Pro-GLP-1, a Pro-drug of GLP-1, is neuroprotective in cerebral ischemia
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Pro-GLP-1 是 GLP-1 的前体药物，对脑缺血具有神经保护作用
DOI：
10.1016/j.ejps.2015.01.010
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发表时间：
2015
影响因子：
4.6
通讯作者：
Luo Xiaoxing
中科院分区：
文献类型：
--
作者：
Zhang Huinan;Meng Jingru;Li Xubo;Zhou Shimeng;Qu Di;Wang Ning;Jia Min;Ma Xue;Luo Xiaoxing
采用聚合物前体药物策略开发了一种长效GLP-1受体（GLP-1 R）激动剂Pro-GLP-1，并在C57 BL/6小鼠中研究了其对缺血性卒中的神经保护作用。在大脑中动脉闭塞（MCAO）手术前，将Pro-GLP-1注射到C57 BL/6小鼠的腹腔中，每天一次，持续7天。缺血24 h后进行神经功能缺损评分和TTC染色。结果表明，Pro-GLP-1在小鼠的血浆和脑中缓慢降解，甚至在给药后12 h仍可检测到GLP-1。Pro-GLP-1在经历MCAO的C57 BL/6小鼠中具有显著的神经保护作用。在培养的皮层神经元中，用Pro-GLP-1处理减弱了由氧-葡萄糖剥夺（OGD）诱导的细胞凋亡。Pro-GLP-1的神经保护作用可被选择性GLP-1受体拮抗剂和用shRNA敲低GLP-1受体阻断。然而，Pro-GLP-1对血糖和胰岛素水平没有影响，这表明神经保护是通过激活脑中的GLP-1受体介导的。Pro-GLP-1修复促凋亡蛋白和抗凋亡蛋白的平衡，并降低caspase-3的表达。其抗凋亡作用是通过cAMP/PKA和PI 3 K/Akt途径介导的。我们的研究提供了证据表明，用Pro-GLP-1预处理MCAO小鼠通过阻断细胞凋亡发挥神经保护作用，并且Pro-GLP-1可能是预防缺血性卒中的潜在神经保护剂候选物。
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.