Oleoylethanolamide Protects against Acute Ischemic Stroke by Promoting PPARα-Mediated Microglia/Macrophage M2 Polarization.
Oleoylethanolamide Protects against Acute Ischemic Stroke by Promoting PPARα-Mediated Microglia/Macrophage M2 Polarization.
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DOI：
10.3390/ph16040621
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发表时间：
2023-04-20
期刊：
影响因子：
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通讯作者：
Yang L
中科院分区：
文献类型：
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作者：
Li Y;Zhang Y;Wang Q;Wu C;Du G;Yang L
油酰乙醇胺(OEA)已被证明是一种可行的缺血性卒中保护剂。然而，OEA提供的神经保护机制仍然难以捉摸。本研究旨在探讨氧化苦参碱对脑缺血后过氧化物酶体增殖物激活受体α(PPARα)介导的小胶质细胞M2极化的神经保护作用。在野生型(WT)或PPARα基因敲除(KO)小鼠上复制一过性大脑中动脉闭塞(TMCAO)1h。以小鼠小胶质瘤细胞(BV2)、小胶质细胞和原代培养的小胶质细胞为研究对象，观察OEA对小胶质细胞的直接作用。用共培养系统进一步阐明OEA对小胶质细胞极化和缺血神经元命运的影响。OEA可促进WT鼠小胶质细胞由炎症性M1表型向保护性M2表型转变，并增强PPARα与精氨酸酶1(Arg1)和YM1启动子的结合，但对KO小鼠无明显影响。值得注意的是，OEA治疗引起的M2小胶质细胞增加与缺血性中风后神经元存活密切相关。体外研究证实，OEA通过PPARα使BV2小胶质细胞由脂多糖诱导的M1样表型转变为M2样表型。此外，OEA激活原代小胶质细胞中的PPARα导致M2保护表型，从而提高了神经元在共培养系统中抵抗缺氧-葡萄糖剥夺(OGD)的存活。我们的研究结果证明了海参皂苷通过激活PPARα信号增强小胶质细胞M2极化以保护邻近神经元的新作用，这是海参皂苷抗脑缺血损伤的新机制。因此，OEA可能是一种很有前途的卒中治疗药物，靶向PPARα介导的M2小胶质细胞可能是治疗缺血性卒中的新策略。
Oleoylethanolamide (OEA) has been demonstrated to be a feasible protectant in ischemic stroke. However, the mechanism for OEA-afforded neuroprotection remains elusive. The present study aimed to investigate the neuroprotective effects of OEA on peroxisome proliferator-activated receptor α (PPARα)-mediated microglia M2 polarization after cerebral ischemia. Transient middle cerebral artery occlusion (tMCAO) was induced for 1 h in wild-type (WT) or PPARα-knock-out (KO) mice. Mouse small glioma cells (BV2) microglia and primary microglia cultures were used to evaluate the direct effect of OEA on microglia. A coculture system was used to further elucidate the effect of OEA on microglial polarization and ischemic neurons’ fate. OEA promoted the microglia switch from an inflammatory M1 phenotype to the protective M2 phenotype and enhanced the binding of PPARα with the arginase1 (Arg1) and Ym1 promoter in WT mice but not in KO mice after MCAO. Notably, the increased M2 microglia caused by OEA treatment were strongly linked to neuron survival after ischemic stroke. In vitro studies confirmed that OEA shifted BV2 microglia from (lipopolysaccharide) LPS-induced M1-like to M2-like phenotype through PPARα. Additionally, the activation of PPARα in primary microglia by OEA led to an M2 protective phenotype that enhanced neuronal survival against oxygen-glucose deprivation (OGD) in the coculture systems. Our findings demonstrate the novel effects of OEA in enhancing microglia M2 polarization to protect neighboring neurons by activating the PPARα signal, which is a new mechanism of OEA against cerebral ischemic injury. Therefore, OEA might be a promising therapeutic drug for stroke and targeting PPARα-mediated M2 microglia may represent a new strategy to treat ischemic stroke.