Long Zhengyang, Huang Yixun, Lin Tao, Xiao Shanying, Chen Kaiye, Ying Jiahao, Wang Ke, Zhang Zhe, Wu Long
Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, China.
Phytother Res. 2025 May;39(5):2324-2338. doi: 10.1002/ptr.8469. Epub 2025 Mar 26.
To investigate the potential of emodin in promoting nerve regeneration following PNI by targeting macrophage polarization, NLRP3 inflammasome activation, autophagy, and the EGFR/PI3K/Akt/mTOR pathway. A cohort of 78 male Sprague-Dawley rats was used to develop models of sciatic nerve damage, with an additional 18 rats in the sham surgery group. The rats were randomly assigned to eight groups: Sham, Control, PNI + Emodin (20 mg/kg), PNI + Emodin (80 mg/kg), PNI + MCC950 (10 mg/kg), PNI + Rapamycin (2 mg/kg), PNI + Emodin (80 mg/kg) + 3-MA (15 mg/kg), and PNI + Emodin (80 mg/kg) + NSC 228155 (5 mg/kg). Emodin was administered intragastrical daily, while the inhibitors or agonist were administered via intraperitoneal injection, as per the respective dosages and schedules. The treatment period included assessments of nerve regeneration and functional recovery, such as histological staining, immunofluorescence for cellular markers, TEM for ultrastructural changes, SFI for functional recovery, and western blot analysis for autophagy and inflammatory proteins. IF and TEM images showed that emodin enhanced axonal and myelin regeneration. Histological analysis revealed emodin reduced muscular atrophy and collagen deposition. Emodin decreased pro-inflammatory macrophage markers (CD68) while increasing M2 markers (CD206), inhibited the NLRP3 inflammasome, and reduced IL-1β and caspase-1. It activated autophagy in Schwann cells, with increased LC3-II levels. Network pharmacology and molecular docking identified EGFR in the PI3K/AKT/mTOR pathway as a key target, with emodin inhibiting EGFR activation. This study reveals that emodin promotes early nerve recovery by enhancing functional outcomes, axonal remyelination, and reducing muscle atrophy. It boosts autophagy in Schwann cells, inhibits NLRP3 inflammasome activation, and promotes M2 macrophage polarization. These effects are closely related to the EGFR/PI3K/AKT/mTOR pathway.
通过靶向巨噬细胞极化、NLRP3炎性小体激活、自噬以及EGFR/PI3K/Akt/mTOR信号通路，研究大黄素在促进周围神经损伤（PNI）后神经再生方面的潜力。选取78只雄性Sprague-Dawley大鼠建立坐骨神经损伤模型，另有18只大鼠作为假手术组。将大鼠随机分为八组：假手术组、对照组、PNI+大黄素（20mg/kg）组、PNI+大黄素（80mg/kg）组、PNI+MCC950（10mg/kg）组、PNI+雷帕霉素（2mg/kg）组、PNI+大黄素（80mg/kg）+3-MA（15mg/kg）组以及PNI+大黄素（80mg/kg）+NSC 228155（5mg/kg）组。大黄素每日经胃内给药，而抑制剂或激动剂则按照各自的剂量和给药方案经腹腔注射。治疗期间进行了神经再生和功能恢复评估，包括组织学染色、细胞标志物免疫荧光检测、超微结构变化的透射电镜检测、功能恢复的坐骨神经功能指数（SFI）检测以及自噬和炎症蛋白的蛋白质印迹分析。免疫荧光和透射电镜图像显示大黄素增强了轴突和髓鞘再生。组织学分析表明大黄素减少了肌肉萎缩和胶原沉积。大黄素降低了促炎巨噬细胞标志物（CD68），同时增加了M2标志物（CD206），抑制了NLRP3炎性小体，并降低了IL-1β和半胱天冬酶-1。它激活了雪旺细胞中的自噬，使LC3-II水平升高。网络药理学和分子对接确定PI3K/AKT/mTOR信号通路中的EGFR为关键靶点，大黄素可抑制EGFR激活。本研究表明，大黄素通过改善功能结果、促进轴突再髓鞘化和减少肌肉萎缩来促进早期神经恢复。它增强了雪旺细胞中的自噬，抑制了NLRP3炎性小体激活，并促进了M2巨噬细胞极化。这些作用与EGFR/PI3K/AKT/mTOR信号通路密切相关。
