Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonist exendin-4 (Ex-4), a drug that has been used in the clinical treatment of type 2 diabetes mellitus, also confers a neuroprotective effect against stroke. Although GLP-1 analogs were reported to induce sustained insulin secretion and glucose tolerance improved after cessation of treatment, no study has revealed whether Ex-4 exerts sustained neuroprotection against stroke and the underlying mechanism after treatment cessation. In this study, mice were pretreated with Ex-4 for 7 days, and middle cerebral artery occlusion (MCAO) was performed on different days after cessation of Ex-4 treatment. Ex-4 ameliorated neurological dysfunction and reduced the infarct volume induced by MCAO. These protective effects lasted for 6 days after the cessation of Ex-4 treatment and were associated with sustained upregulation of PI3K, AKT, mTOR, and HIF-1α levels, as well as HIF-1α downstream genes. Knockdown of GLP-1R or HIF-1α in the brain by short hairpin RNA abolished Ex-4 treatment-mediated neuroprotection. In normal mice, Ex-4 treatment led to instant upregulation of p-PI3K, p-AKT, p-mTOR, and HIF-1α expression levels, which quickly returned to normal after cessation of Ex-4 treatment, while the expression levels of insulin growth factor-1 receptor (IGF-1R) remained high for 6 days after Ex-4 cessation. Additionally, Ex-4 did not directly induce IGF-1 production, which was only induced by MCAO. Ex-4 induces extended cerebral ischemic tolerance. This neuroprotective effect is associated with activation of GLP-1R and upregulation of IGF-1R in the brain, and the latter then activates the PI3K/AKT/mTOR/HIF-1 signaling pathway via binding to IGF-1 secreted from the ischemic brain.

胰高血糖素样肽-1 (GLP-1) 受体 (GLP-1R) 激动剂 exendin-4 (Ex-4) 是一种已用于临床治疗 2 型糖尿病的药物，对中风也具有神经保护作用. 尽管据报道 GLP-1 类似物在停止治疗后诱导持续的胰岛素分泌和葡萄糖耐量改善，但没有研究表明 Ex-4 是否对中风发挥持续的神经保护作用以及治疗停止后的潜在机制。在这项研究中，小鼠用 Ex-4 预处理 7 天，并在停止 Ex-4 治疗后的不同天进行大脑中动脉闭塞 (MCAO)。Ex-4 改善了神经功能障碍并减少了由 MCAO 引起的梗死体积。这些保护作用在 Ex-4 治疗停止后持续 6 天，并且与 PI3K、AKT、mTOR 和 HIF-1α 水平以及 HIF-1α 下游基因的持续上调有关。通过短发夹 RNA 敲低大脑中的 GLP-1R 或 HIF-1α 消除了 Ex-4 治疗介导的神经保护作用。在正常小鼠中，Ex-4 治疗导致 p-PI3K、p-AKT、p-mTOR 和 HIF-1α 表达水平立即上调，在停止 Ex-4 治疗后迅速恢复正常，而Ex-4 停止后，胰岛素生长因子-1 受体 (IGF-1R) 保持高位 6 天。此外，Ex-4 不直接诱导 IGF-1 的产生，这仅由 MCAO 诱导。Ex-4 诱导延长的脑缺血耐受性。