Xia Xiaomei, Chen Wenli, Zhou Ting, Zhou Fang, Lu Can, Yan Zhenzhuang, Zhao Qin, Su Qinglun
Department of Rehabilitation Medicine, The First Affiliated Hospital of Kangda College of Nanjing Medical University/The First People's Hospital of Lianyungang, Lianyungang 222000 China; Department of Rehabilitation Medicine, Kangda College of Nanjing Medical University, Lianyungang 222000 China.
Department of Rehabilitation Medicine, ZhongDa Hospital Southeast University, Nanjing 210009 China.
Int Immunopharmacol. 2025 Mar 6;149:114148. doi: 10.1016/j.intimp.2025.114148. Epub 2025 Feb 3.
Following an ischemic stroke, neuroinflammation is triggered and is often typified by microglial activation. According to recent research, increased glycolysis metabolism frequently occurs when microglia become activated in an inflammatory response. In this study, we found that the PKM2 expression of microglia was gradually increased during the activation of microglia in ischemic stroke. TEPP-46, the activator of PKM2, enhanced the M2 polarization and promoted phagocytosis of microglia both in vivo and in vitro. Meanwhile, TEPP-46 administration ameliorated neuroinflammation and neuronal injuries and reduced the infarct volume of tMCAO mice. Mechanistically, we demonstrated that TEPP-46 suppressed the nuclear translocation of PKM2 and the interaction of PKM2 and HIF-1α, and inhibited glycolysis of microglia. According to our research, PKM2 modulation in microglia may be a viable therapeutic approach to lessen neuroinflammation following ischemic stroke, and TEPP-46 may be able to polarize microglia from an M1 to an M2 phenotype after ischemia/reperfusion damage.
缺血性中风后，神经炎症被触发，通常以小胶质细胞激活为特征。根据最近的研究，当小胶质细胞在炎症反应中被激活时，糖酵解代谢经常增加。在本研究中，我们发现缺血性中风时小胶质细胞激活过程中PKM2表达逐渐增加。PKM2激活剂TEPP-46在体内和体外均增强了小胶质细胞的M2极化并促进了其吞噬作用。同时，给予TEPP-46可改善神经炎症和神经元损伤，并减少tMCAO小鼠的梗死体积。从机制上讲，我们证明TEPP-46抑制了PKM2的核转位以及PKM2与HIF-1α的相互作用，并抑制了小胶质细胞的糖酵解。根据我们的研究，调节小胶质细胞中的PKM2可能是减轻缺血性中风后神经炎症的一种可行治疗方法，并且TEPP-46可能能够在缺血/再灌注损伤后使小胶质细胞从M1表型极化到M2表型。
