Hu Zhenxin, Xuan Lina, Wu Tingting, Jiang Nizhou, Liu Xiangjun, Chang Jiazhen, Wang Te, Han Nan, Tian Xiliang
Department of Orthopedics, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116027, China.
Int Immunopharmacol. 2023 Jan;114:109616. doi: 10.1016/j.intimp.2022.109616. Epub 2022 Dec 22.
Spinal cord injury (SCI) is a severe injury characterized by neuroinflammation and oxidative stress. Taxifolin is exhibits anti-inflammatory and antioxidative activities in neurologic diseases. However, the roles and mechanisms of taxifolin in neuroinflammation and microglial pyroptosis after SCI remain unclear. The present study aims to investigate the effect of taxifolin on SCI and its potential underlying mechanisms in in vivo and in vitro models. In this study, taxifolin markedly reduced microglial activation mediated oxidative stress, and inhibited the expression of pyroptosis-related proteins (NLRP3, GSDMD, ASC, and Caspase-1) and inflammatory cytokines (IL-1β and IL-18) after SCI, as shown by immunofluorescence staining and western blot assays. In addition, taxifolin promoted axonal regeneration and improved functional recovery after SCI. In vitro studies showed that taxifolin attenuated the activation of microglia and oxidative stress after lipopolysaccharide (LPS) + adenosine-triphosphate (ATP) stimulation in BV2 cells. We also observed that taxifolin inhibited the pyroptosis-related proteins and reduced the release of inflammatory cytokines. Moreover, to explore how taxifolin exerts its effects on microglial pyroptosis and axonal regeneration of neurons, we performed an in vitro study in BV-2 cells and PC12 cells co-culture. The results revealed that taxifolin facilitated axonal regeneration of PC12 cells in co-culture with LPS + ATP-induced BV-2 cells. Mechanistically, taxifolin regulated microglial pyroptosis via the PI3K/AKT signaling pathway. Taken together, these results suggest that taxifolin alleviates neuroinflammation and microglial pyroptosis through the PI3K/AKT signaling pathway after SCI, and promotes axonal regeneration and improves functional recovery, suggesting that taxifolin may represent a potential therapeutic agent for SCI.
脊髓损伤（SCI）是一种以神经炎症和氧化应激为特征的严重损伤。紫杉叶素在神经疾病中表现出抗炎和抗氧化活性。然而，紫杉叶素在SCI后神经炎症和小胶质细胞焦亡中的作用及机制仍不清楚。本研究旨在探讨紫杉叶素在体内和体外模型中对SCI的影响及其潜在的作用机制。在本研究中，免疫荧光染色和蛋白质印迹分析表明，紫杉叶素显著降低了小胶质细胞活化介导的氧化应激，并抑制了SCI后焦亡相关蛋白（NLRP3、GSDMD、ASC和Caspase-1）和炎性细胞因子（IL-1β和IL-18）的表达。此外，紫杉叶素促进了SCI后的轴突再生并改善了功能恢复。体外研究表明，紫杉叶素可减轻脂多糖（LPS）+三磷酸腺苷（ATP）刺激后BV2细胞中小胶质细胞的活化和氧化应激。我们还观察到紫杉叶素抑制了焦亡相关蛋白并减少了炎性细胞因子的释放。此外，为了探究紫杉叶素如何对小胶质细胞焦亡和神经元轴突再生发挥作用，我们在BV-2细胞和PC12细胞共培养体系中进行了体外研究。结果显示，紫杉叶素促进了与LPS + ATP诱导的BV-2细胞共培养的PC12细胞的轴突再生。机制上，紫杉叶素通过PI3K/AKT信号通路调节小胶质细胞焦亡。综上所述，这些结果表明，紫杉叶素在SCI后通过PI3K/AKT信号通路减轻神经炎症和小胶质细胞焦亡，并促进轴突再生和改善功能恢复，提示紫杉叶素可能是一种治疗SCI的潜在药物。
