JAK2-STAT3信号通路在树鼩脑缺血后适应中r的作用机制

摘要

AIM:To investigate the regulatory effect of JAK 2-STAT3 signaling pathway on the neuroprotection of ischemic postconditioning (IPoC) in tree shrews, and to explore the mechanisms of cerebral injury deterioration after in-hibiting the JAK2-STAT3 pathway .METHODS:The model of thrombotic cerebral ischemia was induced by photochemical reaction in tree shrews and the IPoC was established at 4 h after ischemia followed by clipping ipsilateral common carotid ar-tery on the ischemia side for 5 min ( 3 times ) .After IPoC and intracerebroventricular injection of AG 490 ( JAK2 inhibi-tor), the changes of cerebral infarction area were detected by TTC staining , and the histological and ultrastructural changes of cortical neurons were observed under light and electron microscopes , respectively .The protein levels of t-STAT3 and p-STAT3 in the cortical tissue were determined by Western blot .RESULTS:The neuronal pycnosis , mitochondrial swelling and vanish of the mitochondrial cristae were found in cortical cortex , and the infarction area was (24.78 ±3.30)%at 24 h after cerebral ischemia .Meanwhile, the phosphorylation level of STAT 3 protein in the cortical tissue was significantly in-creased (P<0.01).The cortical neuronal damage and mitochondrial swelling were decreased after IPoC , the area of cere-bral infarction was significantly reduced to (17.67 ±1.83)%(P<0.01), and the phosphorylation level of STAT3 protein was further increased ( P<0.01 ) .However , the neuronal damage was aggravated , the infarction area was expanded to (23.85 ±2.77)%(P<0.05) after treatment with AG490, and the phosphorylation level of STAT3 protein was also signif-icantly reduced ( P <0.05 ) .CONCLUSION: IPoC may reduce cerebral injury by regulating the phosphorylation of STAT3 protein, and inhibition of JAK2-STAT3 signaling pathway may counteract the cerebral protective effect of IPoC and aggravate brain injury .%目的:观察JAK2-STAT3信号转导通路在树鼩缺血后适应(ischemic postconditioning,IPoC)神经保护中的调控作用,探讨阻断JAK2-STAT3通路后脑损伤加重的机制.方法:通过光化学反应建立树鼩血栓性脑缺血模型;于缺血后4 h夹闭患侧颈总动脉3次(每次5 min)实施IPoC.于IPoC前10 min侧脑室注射AG490(JAK2抑制剂)后,采用TTC染色观察树鼩脑梗死面积的变化,通过HE染色和电镜观察脑皮层神经元形态改变及超微结构变化,应用Western blot检测IPoC及AG490处理后皮层t-STAT3和p-STAT3蛋白水平的变化.结果:缺血24 h,皮层神经元固缩,线粒体肿胀,嵴溶解;脑梗死面积占半脑面积的(24.78±3.30)%;此时皮层神经元STAT3磷酸化水平明显增高(P<0.01).IPoC后皮层神经元损伤减轻,线粒体肿胀改善,脑梗死面积占半脑面积的百分比减小为(17.67±1.83)%(P<0.01),STAT3磷酸化水平进一步增高(P<0.01).然而,给予AG490处理后,皮层神经元损伤加重,脑梗死面积再次增大为(23.85±2.77)%(P<0.05),STAT3磷酸化水平则明显降低(P<0.05).结论:IPoC可能通过调控STAT3的磷酸化而减轻树鼩缺血性脑损伤,抑制JAK2-STAT3信号通路可抵消IPoC的保护效应而加重脑损伤.