Department of Neurology, The Second Hospital Affiliated to Shanxi Medical University, Taiyuan, 030000, Shanxi, China.
Shanxi Medical University, Taiyuan, 030000, Shanxi, China.
Transl Stroke Res. 2024 Feb;15(1):1-15. doi: 10.1007/s12975-022-01105-5. Epub 2022 Nov 17.
M1 microglial activation is crucial for the pathogenesis of early brain injury (EBI) following subarachnoid hemorrhage (SAH), and there is growing evidence that glucose metabolism is frequently involved in microglial activation. However, the molecular mechanism of glycolysis and its role in M1 microglial activation in the context of EBI are not yet fully understood. In this study, firstly, the relationship between aerobic glycolysis and M1 microglial activation as well as SAH-induced EBI was researched in vivo. Then, intervention on mammalian target of rapamycin (mTOR) was performed to investigate the effects on glycolysis-dependent M1 microglial activation and EBI and its relationship with hypoxia-inducible factor-1α (HIF-1α) in vivo. Next, Hif-1α was inhibited to analyze its role in aerobic glycolysis, M1 microglial activation, and EBI in vivo. Lastly, both in vivo and in vitro, mTOR inhibition and Hif-1α enhancement were administered simultaneously, and the combined effects were further confirmed again. The results showed that aerobic glycolysis and M1 microglial polarization were increased after SAH, and glycolytic inhibition could attenuate M1 microglial activation and EBI. Inhibition of mTOR reduced glycolysis-dependent M1 microglial polarization and EBI severity by down-regulating HIF-1α expression, while enhancement had the opposite effects. Blockading HIF-1α had the similar effects as suppressing mTOR, while HIF-1α agonist worked against mTOR antagonist when administered simultaneously. In conclusion, the present study showed new evidence that aerobic glycolysis induced by mTOR/HIF-1α might promote EBI after SAH by activating M1 microglia. This finding provided new insights for the treatment of EBI.
M1 小胶质细胞的激活对于蛛网膜下腔出血 (SAH) 后早期脑损伤 (EBI) 的发病机制至关重要，越来越多的证据表明葡萄糖代谢经常参与小胶质细胞的激活。然而，糖酵解的分子机制及其在 EBI 中小胶质细胞 M1 激活中的作用尚不完全清楚。在这项研究中，首先在体内研究了有氧糖酵解与 M1 小胶质细胞激活以及 SAH 诱导的 EBI 之间的关系。然后，对雷帕霉素靶蛋白 (mTOR) 进行干预，以研究其对糖酵解依赖性 M1 小胶质细胞激活和 EBI 的影响及其与缺氧诱导因子-1α (HIF-1α) 的关系。接下来，抑制 Hif-1α 以分析其在体内有氧糖酵解、M1 小胶质细胞激活和 EBI 中的作用。最后，在体内和体外同时给予 mTOR 抑制和 Hif-1α 增强，并再次进一步证实联合作用。结果表明，SAH 后有氧糖酵解和 M1 小胶质细胞极化增加，糖酵解抑制可减轻 M1 小胶质细胞激活和 EBI。抑制 mTOR 通过下调 HIF-1α 表达减少糖酵解依赖性 M1 小胶质细胞极化和 EBI 严重程度，而增强则有相反的效果。阻断 HIF-1α 具有与抑制 mTOR 相似的效果，而 HIF-1α 激动剂与 mTOR 拮抗剂同时给药时则起到拮抗作用。总之，本研究提供了新的证据，表明 mTOR/HIF-1α 诱导的有氧糖酵解可能通过激活 M1 小胶质细胞促进 SAH 后的 EBI。这一发现为 EBI 的治疗提供了新的思路。
