胰高血糖素样肽-1受体介导星形胶质细胞“代谢记忆”诱导脑缺血耐受的分子机制

脑缺血引起的能量代谢障碍是导致神经细胞损伤和神经功能缺失的重要原因。星形胶质细胞的能量代谢途径对于维持缺血时神经元活动至关重要，与神经元缺血耐受性的产生密切相关。我们前期研究发现激动GLP-1受体产生的神经保护作用具有“记忆效应”，在停药后第6天仍能够显著减少急性缺血再灌注损伤后的梗死体积，但机制不清。研究发现，星形胶质细胞上存在GLP-1受体，缺血性损伤可增加星形胶质细胞GLP-1受体表达，据此我们提出假说，GLP-1可能通过活化星形胶质细胞的能量代谢途径产生“代谢记忆”，诱导脑缺血耐受，在后续缺血损伤时为神经元活动提供能量，发挥脑缺血保护作用的“记忆效应”。本项目拟在整体和离体水平证实GLP-1受体在星形胶质细胞能量代谢过程中的重要功能，阐明“代谢记忆”产生的分子机制。旨在揭示星形胶质细胞产生“代谢记忆”的新机制，为药物诱导脑缺血耐受发现新靶标，为缺血性脑损伤提供新的预防和治疗策略。

Metabolic disorders caused by cerebral ischemia are important reasons for neuronal damage and functional deficits. Energy metabolism in astrocytes is required to sustain neuronal activity during ischemia, which is closely related to brain ischemic tolerance. Our previous studies found that the neuroprotective effects of GLP-1 receptor activation showed "memory effect". It showed GLP-1R agonist significantly reduced infarct volume induced acute ischemia-reperfusion injury on 6 days after GLP-1R agonist treatment stopped, but the mechanism is unclear. Previous results found that GLP-1 receptor expressed in astrocyte. The expression of GLP-1 receptor increased after cerebral ischemia-reperfusion injury. So in this project we proposed hypothesis that the "memory effect" of GLP-1 maybe induced by the activation of energy metabolism in astrocytes. The effect of "metabolic memory" could induce brain ischemic tolerance, which provide energy in follow-up ischemic injury in order to exert "memory neuroprotective effect". In our research, we plan to investigate the important function of GLP-1 receptor in energy metabolism of astrocytes and the molecular mechanisms of astrocyte "metabolism memory effect" mediated by glucagon-like peptide-1 receptor on brain ischemic tolerance. The aim of this study is to reveal the novel mechanism of astrocyte "metabolism memory effect" to explore new target for drug-induced cerebral ischemic tolerance and provide new strategies for prevention and treatment of ischemic brain injury.