Wen Wen, Chen Hao, Dai Yuan, Zhang Shiqi, Zhang Hao, Zhang Haijun, Xiang Junbao, Tang Xueqian, Liu Xiao, Wang Ping, Xu Shijun
State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, PR China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, PR China; Institute of Material Medica Integration and Transformation for Brain Disorders, Chengdu University of Traditional Chinese Medicine, Chengdu, PR China.
State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, PR China; School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, PR China.
J Ethnopharmacol. 2025 Aug 13;353(Pt B):120424. doi: 10.1016/j.jep.2025.120424.
Glycolysis-related microglial polarization contributes to the migraine (CM), which are closely associated with the PKM2-STAT3/NF-κB axis. Viticis Fructus has been historically prescribed in Traditional Chinese Medicine for alleviating CM, casticin as the active compound of Viticis Fructus has the therapeutic potential for CM.
To investigate the mechanism of casticin in treating CM, highlighting the role of PKM2-STAT3/NF-κB axis in mediating microglial polarization and glycolysis.
The recurrent nitroglycerin (NTG) injections were used to establish CM rat models, then nociceptive thresholds, migraine-like symptoms, blood-brain barrier (BBB) integrity, the IL-17 levels and other inflammatory mediators, glycolysis, and the PKM2-STAT3/NF-κB axis were assessments. Next, IL-17A-treated BV-2 cells were used to demonstrate the effects of casticin on microglial polarization, glycolysis, and the PKM2-STAT3/NF-κB axis. Last, the SR1001 and brodalumab were used in NTG-injected rats and IL-17A-stimulated BV2 cells for reverse verification.
Casticin reduced IL-17 entry into the TNC, suppressed inflammatory mediator release, decreased CGRP levels, inhibited microglial inflammatory polarization, reduced the level of glycolysis. Moreover, casticin markedly inhibited the PKM2-STAT3/NF-κB axis in the TNC, which jointly validated by WB and immunofluorescence colocalization. Additionally, SR1001 and brodalumab reversed the effects of Casticin in vivo and in vitro, which was mainly accomplished via PKM2-dependent microglial polarization.
Casticin alleviated pain sensitization and CM-like symptoms in CM rats by targeting IL-17-mediated microglial polarization and glycolysis via inhibition of the PKM2-STAT3/NF-κB axis, which explains the mechanism by which casticin relieves CM.
与糖酵解相关的小胶质细胞极化促成偏头痛（CM），这与PKM2-STAT3/NF-κB轴密切相关。中药历史上一直使用蔓荆子来缓解CM，蔓荆子的活性成分紫花牡荆素具有治疗CM的潜力。
研究紫花牡荆素治疗CM的机制，突出PKM2-STAT3/NF-κB轴在介导小胶质细胞极化和糖酵解中的作用。
采用反复注射硝酸甘油（NTG）建立CM大鼠模型，然后评估痛觉阈值、偏头痛样症状、血脑屏障（BBB）完整性、IL-17水平和其他炎症介质、糖酵解以及PKM2-STAT3/NF-κB轴。接下来，使用IL-17A处理的BV-2细胞来证明紫花牡荆素对小胶质细胞极化、糖酵解和PKM2-STAT3/NF-κB轴的影响。最后，将SR1001和布罗达单抗用于NTG注射的大鼠和IL-17A刺激的BV2细胞进行反向验证。
紫花牡荆素减少IL-17进入三叉神经节（TNC），抑制炎症介质释放，降低降钙素基因相关肽（CGRP）水平，抑制小胶质细胞炎症极化，降低糖酵解水平。此外，紫花牡荆素显著抑制TNC中的PKM2-STAT3/NF-κB轴，这通过蛋白质免疫印迹（WB）和免疫荧光共定位共同验证。此外，SR1001和布罗达单抗在体内和体外逆转了紫花牡荆素的作用，这主要是通过PKM2依赖性小胶质细胞极化实现的。
紫花牡荆素通过抑制PKM2-STAT3/NF-κB轴靶向IL-17介导的小胶质细胞极化和糖酵解，减轻CM大鼠的疼痛敏化和CM样症状，这解释了紫花牡荆素缓解CM的机制。
