Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, PR China.
Department of Neurosurgery, Xijing Hospital, Xi'an, 710000, Shaanxi, PR China.
Exp Cell Res. 2023 Dec 15;433(2):113829. doi: 10.1016/j.yexcr.2023.113829. Epub 2023 Oct 24.
Chronic subdural hematoma (CSDH) remains a neurosurgical condition and a healthy burden especially in elderly patients. This study focuses on the functions of rapamycin and its related molecular mechanisms in CSDH management. A rat model of CSDH was induced, which developed significant hematoma on day 5 after operation. The rats were treated with rapamycin or atorvastatin, a drug with known effect on hematoma alleviation, or treated with rapamycin and atorvastatin in combination. The atorvastatin or rapamycin treatment reduced the hematoma development, blood-brain barrier permeability, neurological dysfunction in CSDH rats, and the combination treatment showed more pronounced effects. Human brain microvascular endothelial cells hCMEC/D3 were stimulated by hematoma samples to mimic a CSDH condition in vitro. The drug treatments elevated the cell junction-related factors and reduced the pro-inflammatory cytokines both in rat hematoma tissues and in hCMEC/D3 cells. Rapamycin suppressed the mTOR and STAT3 signaling pathways. Overexpression of mTOR or the STAT3 agonist suppressed the alleviating effects of rapamycin on CSDH. In summary, this study demonstrates that rapamycin promotes hematoma resorption and enhances endothelial cell function by suppressing the mTOR/STAT3 signaling.
慢性硬脑膜下血肿（CSDH）仍然是一种神经外科疾病，尤其是在老年患者中，是一个健康负担。本研究重点关注雷帕霉素及其在 CSDH 管理中的相关分子机制的作用。建立了 CSDH 大鼠模型，该模型在手术后第 5 天出现明显血肿。用雷帕霉素或阿托伐他汀（一种已知可减轻血肿的药物）或雷帕霉素和阿托伐他汀联合治疗大鼠。阿托伐他汀或雷帕霉素治疗可减少 CSDH 大鼠的血肿发展、血脑屏障通透性和神经功能障碍，联合治疗效果更明显。用人脑微血管内皮细胞 hCMEC/D3 刺激血肿样本，在体外模拟 CSDH 条件。药物治疗可提高大鼠血肿组织和 hCMEC/D3 细胞中与细胞连接相关的因子，并降低促炎细胞因子。雷帕霉素抑制 mTOR 和 STAT3 信号通路。过表达 mTOR 或 STAT3 激动剂可抑制雷帕霉素对 CSDH 的缓解作用。综上所述，本研究表明，雷帕霉素通过抑制 mTOR/STAT3 信号通路促进血肿吸收和增强内皮细胞功能。
