Stroke remains one of the most common causes of death and disability worldwide. Several preclinical studies demonstrated that the brain can be effectively protected against ischaemic stroke by two seemingly distinct treatments: remote ischaemic conditioning (RIC), involving cycles of ischaemia/reperfusion applied to a peripheral organ or tissue, or by systemic administration of glucagon-like-peptide-1 (GLP-1) receptor (GLP-1R) agonists. The mechanisms underlying RIC- and GLP-1-induced neuroprotection are not completely understood. In this study, we tested the hypothesis that GLP-1 mediates neuroprotection induced by RIC and investigated the effect of GLP-1R activation on cerebral blood vessels, as a potential mechanism of GLP-1-induced protection against ischaemic stroke. A rat model of ischaemic stroke (90 min of middle cerebral artery occlusion followed by 24-h reperfusion) was used. RIC was induced by 4 cycles of 5 min left hind limb ischaemia interleaved with 5-min reperfusion periods. RIC markedly (by ~ 80%) reduced the cerebral infarct size and improved the neurological score. The neuroprotection established by RIC was abolished by systemic blockade of GLP-1R with a specific antagonist Exendin(9–39). In the cerebral cortex of GLP-1R reporter mice, ~ 70% of cortical arterioles displayed GLP-1R expression. In acute brain slices of the rat cerebral cortex, activation of GLP-1R with an agonist Exendin-4 had a strong dilatory effect on cortical arterioles and effectively reversed arteriolar constrictions induced by metabolite lactate or oxygen and glucose deprivation, as an ex vivo model of ischaemic stroke. In anaesthetised rats, Exendin-4 induced lasting increases in brain tissue PO₂, indicative of increased cerebral blood flow. These results demonstrate that neuroprotection against ischaemic stroke established by remote ischaemic conditioning is mediated by a mechanism involving GLP-1R signalling. Potent dilatory effect of GLP-1R activation on cortical arterioles suggests that the neuroprotection in this model is mediated via modulation of cerebral blood flow and improved brain perfusion.

中风仍然是全世界最常见的死亡和残疾原因之一。几项临床前研究表明，通过两种看似不同的治疗方法可以有效地保护大脑免受缺血性中风：远程缺血调理（RIC），涉及应用于外周器官或组织的缺血/再灌注循环，或通过全身给予胰高血糖素样治疗。肽-1 (GLP-1) 受体 (GLP-1R) 激动剂。RIC 和 GLP-1 诱导的神经保护机制尚不完全清楚。在这项研究中，我们检验了 GLP-1 介导 RIC 诱导的神经保护的假设，并研究了 GLP-1R 激活对脑血管的影响，作为 GLP-1 诱导的缺血性卒中保护的潜在机制。使用大鼠缺血性中风模型（大脑中动脉闭塞 90 分钟，然后再灌注 24 小时）。RIC 由 4 个周期的 5 分钟左后肢缺血和 5 分钟再灌注周期交错诱导。RIC 显着（约 80%）减少了脑梗死面积并提高了神经系统评分。RIC 建立的神经保护作用被一种特异性拮抗剂 Exendin (9-39) 全身性阻断 GLP-1R 所消除。在 GLP-1R 报告小鼠的大脑皮质中，约 70% 的皮质小动脉表现出 GLP-1R 表达。在大鼠大脑皮层的急性脑切片中，用激动剂 Exendin-4 激活 GLP-1R 对皮质小动脉有很强的扩张作用，并有效地逆转代谢物乳酸或氧气和葡萄糖剥夺引起的小动脉收缩，作为体外模型缺血性中风。₂、提示脑血流量增加。这些结果表明，通过远程缺血调节建立的针对缺血性中风的神经保护是由涉及 GLP-1R 信号传导的机制介导的。GLP-1R 激活对皮质小动脉的有效扩张作用表明，该模型中的神经保护是通过调节脑血流和改善脑灌注来介导的。