Hou Boru, Li Donghai, Wang Dengfeng, Jiang Cheng, Wang Gang, Wang Dong, Yan Guizhong, Guo Xiumei, Zhao Lixia, Wan Zhuangzhuang, Fan Chenlong, Cao Wencheng, Ren Haijun
Department of Neurosurgery, Lanzhou University Second Hospital, Lanzhou, China.
Gansu Key Laboratory of Biomonitoring and Bioremediation for Environmental Pollution, School of Life Sciences, Lanzhou University, Lanzhou, China.
Neuroscience. 2023 Aug 21;526:74-84. doi: 10.1016/j.neuroscience.2023.05.021. Epub 2023 Jun 7.
Ischemic stroke is one of the main causes of serious disability and death worldwide. NLRP3 inflammasome is an intracellular pattern recognition receptor composed of polyprotein complex, which participates in mediating a series of inflammatory responses and is considered as a potential target for the treatment of ischemic stroke. Vinpocetine, a derivative of vincamine, has been widely used in the prevention and treatment of ischemic stroke. However, the therapeutic mechanism of vinpocetine is not clear, and its effect on NLRP3 inflammasome remains to be determined. In this study, we used the mouse model of transient middle cerebral artery occlusion (tMCAO) to simulate the occurrence of ischemic stroke. Different doses of vinpocetine (5, 10, 15 mg/kg/d) were injected intraperitoneally for 3 days after ischemia-reperfusion in mice. The effects of different doses of vinpocetine on the degree of ischemia-reperfusion injury in mice were observed by TTC staining and modified neurological severity score scale, and the optimal dose was determined. Then, based on this optimal dose, we observed the effects of vinpocetine on apoptosis, microglial proliferation and NLRP3 inflammasome. In addition, we compared the effects of vinpocetine and MCC950 (a specific inhibitor of NLRP3 inflammasome) on NLRP3 inflammasome. Our results show that vinpocetine can effectively reduce the infarct volume and promote the recovery of behavioral function in stroke mice, and the maximal beneficial effects were observed at the dose of 10 mg/kg/d. Vinpocetine can effectively inhibit the apoptosis of peri-infarct neurons, promote the expression of Bcl-2, inhibit the expression of Bax and Cleaved Caspase-3, and reduce the proliferation of peri-infarct microglia. In addition, vinpocetine, like MCC950, can reduce the expression of NLRP3 inflammasome. Therefore, vinpocetine can effectively alleviate the ischemia-reperfusion injury in mice, and the inhibition of NLRP3 inflammasome may be an important therapeutic mechanism of vinpocetine.
缺血性中风是全球严重致残和死亡的主要原因之一。NLRP3炎性小体是一种由多蛋白复合物组成的细胞内模式识别受体，参与介导一系列炎症反应，被认为是缺血性中风治疗的潜在靶点。长春西汀是长春胺的衍生物，已广泛应用于缺血性中风的预防和治疗。然而，长春西汀的治疗机制尚不清楚，其对NLRP炎性小体的影响仍有待确定。在本研究中，我们使用短暂性大脑中动脉闭塞（tMCAO）小鼠模型来模拟缺血性中风的发生。在小鼠缺血再灌注后，腹腔注射不同剂量的长春西汀（5、10、15mg/kg/d），持续3天。通过TTC染色和改良神经功能缺损评分量表观察不同剂量长春西汀对小鼠缺血再灌注损伤程度的影响，并确定最佳剂量。然后，基于该最佳剂量，我们观察了长春西汀对细胞凋亡、小胶质细胞增殖和NLRP3炎性小体的影响。此外，我们比较了长春西汀和MCC950（NLRP3炎性小体的特异性抑制剂）对NLRP3炎性小体的影响。我们的结果表明，长春西汀可以有效减少中风小鼠的梗死体积，促进行为功能的恢复，在10mg/kg/d的剂量下观察到最大的有益效果。长春西汀可以有效抑制梗死灶周围神经元的凋亡，促进Bcl-2的表达，抑制Bax和Cleaved Caspase-3的表达，并减少梗死灶周围小胶质细胞的增殖。此外，长春西汀与MCC950一样，可以降低NLRP炎性小体的表达。因此，长春西汀可以有效减轻小鼠的缺血再灌注损伤，抑制NLRP3炎性小体可能是长春西汀的重要治疗机制。
