JAK2-STAT3信号通路在树鼩脑缺血后适应中的作用机制

 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。

Mechanism of JAK2-STAT3 signaling pathway in ischemic postconditio-ning neuroprotection after cerebral ischemia in tree shrews

AIM: To investigate the regulatory effect of JAK2-STAT3 signaling pathway on the neuroprotection of ischemic postconditioning (IPoC) in tree shrews, and to explore the mechanisms of cerebral injury deterioration after inhibiting 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 artery on the ischemia side for 5 min (3 times). After IPoC and intracerebroventricular injection of AG490 (JAK2 inhibitor), 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 STAT3 protein in the cortical tissue was significantly increased (P<0.01). The cortical neuronal damage and mitochondrial swelling were decreased after IPoC, the area of cerebral 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 significantly 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.