Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post Neurotrauma, Neurorepair, and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China.
Department of Neurology, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post Neurotrauma, Neurorepair, and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China.
Exp Neurol. 2023 Oct;368:114474. doi: 10.1016/j.expneurol.2023.114474. Epub 2023 Jul 5.
Neuroinflammation after cerebral ischemia is a key event in progressive brain injury after ischemic stroke. The JAK2/STAT3 pathway is pivotal for neuroinflammation; however, its role in brain senescence after ischemic stroke is unclear. Here, we report that inflammation is increased in the brains of C57BL/6 stroke mice. Treatment of ischemic stroke in adult mice with a JAK kinase inhibitor (AG490) alleviated neurobehavioral defects, reduced brain infarct volume, reduced expression of pro-inflammatory cytokines, and decreased activation of pro-inflammatory microglia. Moreover, AG490 treatment reduced oxidative DNA damage and cellular senescence in the brains of mice following ischemic stroke. Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) were associated with inflammation and senescence. Furthermore, AG490 blocked cGAS/STING/NF-κBp65 expression. Overall, our results indicate that inhibition of JAK2/STAT3 can alleviate the negative neurological consequences of ischemic stroke, likely due to repression of cGAS/STING/NF-κB p65, leading to reduced neuroinflammation and neuronal senescence. Therefore, JAK2/STAT3 may represent a viable therapeutic target for preventing senescence after ischemic stroke.
脑缺血后的神经炎症是缺血性脑卒中后进行性脑损伤的关键事件。JAK2/STAT3 通路对于神经炎症至关重要；然而，其在缺血性脑卒中后脑衰老中的作用尚不清楚。在这里，我们报告 C57BL/6 脑卒中小鼠的大脑中炎症增加。用 JAK 激酶抑制剂 (AG490) 治疗成年小鼠的缺血性脑卒中可减轻神经行为缺陷，减少脑梗死体积，降低促炎细胞因子的表达，并减少促炎小胶质细胞的激活。此外，AG490 处理可减少缺血性脑卒中后小鼠大脑中的氧化 DNA 损伤和细胞衰老。环鸟苷酸-腺苷酸合成酶 (cGAS) 和干扰素基因刺激物 (STING) 与炎症和衰老有关。此外，AG490 阻断了 cGAS/STING/NF-κBp65 的表达。总的来说，我们的结果表明抑制 JAK2/STAT3 可以减轻缺血性脑卒中的负面神经后果，这可能是由于抑制了 cGAS/STING/NF-κB p65，从而减少了神经炎症和神经元衰老。因此，JAK2/STAT3 可能是预防缺血性脑卒中后衰老的一个可行的治疗靶点。
