Department of Neurology, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu 215500, Jiangsu, China.
School of Chinese Medicine and School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China.
Aging (Albany NY). 2023 Aug 30;15(19):10031-10056. doi: 10.18632/aging.204989.
Huangqi Guizhi Wuwu decoction (HGWD) has been demonstrated to ameliorate cerebral ischemia-reperfusion injury in clinical application. Nevertheless, the exact mechanisms of HGWD have not been conclusively elucidated. This study aimed to investigate the potential role and mechanism of HGWD on neurological deficits in a rat model of middle cerebral artery occlusion (MCAO). Our results showed that HGWD significantly alleviated neurological deficits in MCAO rats, evidenced by high mNSS score, reduced cerebral infarction area, and improved brain pathological injury. Besides, HGWD reduced the levels of TNF-α, IL-1β, IL-6, SOD, MDA and GSH in the brain tissue. Further study suggested that HGWD promoted microglia polarization towards M2 by inhibiting M1 activation (Iba1/CD16, iNOS) and enhancing M2 activation (Iba1/CD206, Arg-1). Additionally, HGWD increased dendritic spine density and enhanced levels of synapse marker proteins (PSD95, Synapsin I). HGWD also up-regulated Sirt1 expression while inhibited p-NF-κB, NLRP3, ASC, and cleaved caspase-1 level in the hippocampus of MCAO rats. Sirt1 specific inhibitor EX527 notably weakened the neuroprotective efficacy of HGWD against cerebral ischemia, and significantly abolished its modulation on microglia polarization and synaptic plasticity . Collectively, our findings suggested that HGWD ameliorated neuronal injury in ischemic stroke by modulating M2 microglia polarization and synaptic plasticity, at least partially, via regulating Sirt1/NF-κB/NLRP3 pathway, further supporting HGWD as a potential therapy for neuroprotection after ischemic stroke.
黄芪桂枝五物汤（HGWD）已被证明可改善临床应用中的脑缺血再灌注损伤。然而，HGWD 的确切机制尚未得到明确阐述。本研究旨在探讨 HGWD 在大脑中动脉闭塞（MCAO）大鼠模型中对神经功能缺损的潜在作用和机制。我们的研究结果表明，HGWD 可显著减轻 MCAO 大鼠的神经功能缺损，表现为高 mNSS 评分、减少脑梗死面积和改善脑组织病理损伤。此外，HGWD 降低了脑组织中 TNF-α、IL-1β、IL-6、SOD、MDA 和 GSH 的水平。进一步的研究表明，HGWD 通过抑制 M1 激活（Iba1/CD16、iNOS）和增强 M2 激活（Iba1/CD206、Arg-1）来促进小胶质细胞向 M2 极化。此外，HGWD 增加了树突棘密度，并增强了突触标记蛋白（PSD95、Synapsin I）的水平。HGWD 还上调了 Sirt1 的表达，同时抑制了 MCAO 大鼠海马中 p-NF-κB、NLRP3、ASC 和 cleaved caspase-1 的水平。Sirt1 特异性抑制剂 EX527 显著减弱了 HGWD 对脑缺血的神经保护作用，并显著消除了其对小胶质细胞极化和突触可塑性的调节作用。总之，我们的研究结果表明，HGWD 通过调节 Sirt1/NF-κB/NLRP3 通路，改善 M2 小胶质细胞极化和突触可塑性，从而减轻缺血性中风引起的神经元损伤，这至少部分支持了 HGWD 作为缺血性中风后神经保护的潜在治疗方法。
