Guo Zhe, Zhong Sijia, Bai Jinpeng, Lang Xiuyuan, Cao Minmin, Hu Yang, Qin Xiaoyan, Sun Yingyu
The Emergency Department, The Third Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
Key Laboratory of Ecology and Environment in Minority Areas National Ethnic Affairs Commission, Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing, 100081, China.
Sci Rep. 2025 Jul 1;15(1):21721. doi: 10.1038/s41598-025-05994-y.
Microglial activation, driven by a metabolic shift towards aerobic glycolysis, is implicated in neuroinflammation and neurological disorders like depression. THSG (2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside), derived from Polygonum multiflorum, exhibits anti-inflammatory and neuroprotective properties, but its mechanisms, particularly its impact on microglial metabolism, are largely unexplored. Using a LPS-induced mouse model of neuroinflammation, we observed that THSG significantly ameliorated depression-like behaviors. It suppressed pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6, iNOS), inhibited microglial activation, and reduced key necroptosis markers (phosphorylated RIPK1, RIPK3, and MLKL) in the hippocampus. Importantly, THSG effectively suppressed LPS-induced activation of the glycolytic pathway in the hippocampus, as evidenced by increased ATP levels, decreased lactate levels, reduced activity of key glycolytic enzymes, and decreased expression of PKM2 and HIF-1α, critical players in microglial glycolysis. Further in vitro studies with BV2 microglial cells confirmed that THSG significantly suppressed glycolytic enhancement, promoting a metabolic shift towards oxidative phosphorylation, thus inhibiting inflammatory activation of microglia. Co-culture experiments of BV2 cells and SH-SY5Y cells further corroborated the in vivo findings, demonstrating that THSG mitigated inflammation-induced necroptosis in SH-SY5Y neurons by reducing phosphorylation of RIPK1, RIPK3, and MLKL, thus protecting neurons from damage. Our results highlight the potential of THSG as a therapeutic agent for neuroinflammatory disorders by modulating microglial metabolic reprogramming and inhibiting neuronal necroptosis.
由向有氧糖酵解的代谢转变驱动的小胶质细胞激活与神经炎症和抑郁症等神经系统疾病有关。源自何首乌的THSG（2,3,5,4'-四羟基二苯乙烯-2-O-β-D-葡萄糖苷）具有抗炎和神经保护特性，但其机制，尤其是对小胶质细胞代谢的影响，在很大程度上尚未得到探索。使用脂多糖诱导的神经炎症小鼠模型，我们观察到THSG显著改善了抑郁样行为。它抑制促炎细胞因子的产生（TNF-α、IL-1β、IL-6、iNOS），抑制小胶质细胞激活，并降低海马体中关键的坏死性凋亡标志物（磷酸化RIPK1、RIPK3和MLKL）。重要的是，THSG有效抑制了脂多糖诱导的海马体糖酵解途径的激活，ATP水平升高、乳酸水平降低、关键糖酵解酶活性降低以及PKM2和HIF-1α表达降低证明了这一点，PKM2和HIF-1α是小胶质细胞糖酵解中的关键参与者。对BV2小胶质细胞的进一步体外研究证实，THSG显著抑制糖酵解增强，促进向氧化磷酸化的代谢转变，从而抑制小胶质细胞的炎症激活。BV2细胞和SH-SY5Y细胞的共培养实验进一步证实了体内研究结果，表明THSG通过降低RIPK1、RIPK3和MLKL的磷酸化减轻了SH-SY5Y神经元中炎症诱导的坏死性凋亡，从而保护神经元免受损伤。我们的结果突出了THSG通过调节小胶质细胞代谢重编程和抑制神经元坏死性凋亡作为神经炎症性疾病治疗剂的潜力。
