T-006通过调节Toll样受体4（TLR4）介导的髓样分化因子88（MyD88）/核因子κB（NF-κB）信号通路对阿尔茨海默病模型的抗神经炎症和神经保护作用
Anti-neuroinflammatory and Neuroprotective Effects of T-006 on Alzheimer's Disease Models by Modulating TLR4-Mediated MyD88/ NF-κB Signaling.
作者信息
Chen Haiyun, Chang Xiao, Zhou Jiemei, Zhang Guiliang, Cheng Jiehong, Zhang Zaijun, Xing Jieyu, Yan Chunyan, Liu Zheng
机构信息
School of Pharmacy, Clinical Pharmacy (School of Integrative Pharmacy), Guangdong Pharmaceutical University, Guangzhou, 510006, China.
Institute of New Drug Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Guangzhou, 510632, China.
出版信息
CNS Neurol Disord Drug Targets. 2025;24(5):382-396. doi: 10.2174/0118715273337232241121113048.
INTRODUCTION
Neuroinflammation derived from the activation of the microglia is considered a vital pathogenic factor of Alzheimer's Disease (AD). T-006, a tetramethylpyrazine derivative, has been found to alleviate cognitive deficits via inhibiting tau expression and phosphorylation in AD transgenic mouse models. Recently, T-006 has been proven to dramatically decrease the levels of total Amyloid β (Aβ) peptide and Glial Fibrillary Acidic Protein (GFAP) and suppress the expression of ionized calcium binding adaptor molecule-1 (Iba-1) in APP/PS1 mice. Therefore, we have further investigated the effects of T-006 on neuroinflammation in AD-like pathology.
METHODS
The anti-inflammatory effects of T-006 and its underlying mechanisms were evaluated in Lipopolysaccharide (LPS)-induced AD rats. The potential protective effects against LPS-activated microglia-mediated neurotoxicity were also measured.
RESULTS
T-006 significantly improved the cognitive impairment in LPS-induced AD rats by inhibiting the microglia/astrocyte activation. Further cellular assays found that T-006 significantly reserved the anomalous elevation of inflammatory cytokines in LPS-induced BV2 microglial cells in a concentration-dependent manner, while T-006 treatment alone showed no effects on the normal cultured cells. T-006 also reduced the levels of Toll-like Receptor 4 (TLR4)/Myeloid Differentiation protein-88 (MyD88)/NF-κB signaling-related proteins in BV2 cells exposed to LPS stimulation. TAK242, which selectively inhibits TLR4, slightly lessened the effects of T-006 in LPS-treatment BV2 cells without significance. Importantly, T-006 protected neurons against LPS-induced neuroinflammation by inhibiting the Reactive Oxygen Species (ROS) production and maintaining mitochondrial function.
CONCLUSION
T-006 inhibited TLR4-mediated MyD88/NF-κB signaling pathways to suppress neuroinflammation in the LPS-induced AD rat model.
引言
源自小胶质细胞激活的神经炎症被认为是阿尔茨海默病（AD）的一个重要致病因素。T-006是一种川芎嗪衍生物，在AD转基因小鼠模型中已发现其通过抑制tau蛋白表达和磷酸化来减轻认知缺陷。最近，已证实T-006可显著降低APP/PS1小鼠中总淀粉样β（Aβ）肽和胶质纤维酸性蛋白（GFAP）的水平，并抑制离子钙结合衔接分子1（Iba-1）的表达。因此，我们进一步研究了T-006在AD样病理中对神经炎症的影响。
方法
在脂多糖（LPS）诱导的AD大鼠中评估T-006的抗炎作用及其潜在机制。还测定了其对LPS激活的小胶质细胞介导的神经毒性的潜在保护作用。
结果
T-006通过抑制小胶质细胞/星形胶质细胞激活，显著改善了LPS诱导的AD大鼠的认知障碍。进一步的细胞实验发现，T-006以浓度依赖的方式显著抑制了LPS诱导的BV2小胶质细胞中炎性细胞因子的异常升高，而单独的T-006处理对正常培养的细胞无影响。T-006还降低了暴露于LPS刺激的BV2细胞中Toll样受体4（TLR4）/髓样分化蛋白88（MyD88）/核因子κB（NF-κB）信号相关蛋白的水平。选择性抑制TLR4的TAK242在LPS处理的BV2细胞中对T-006的作用略有减弱，但无显著性差异。重要的是，T-006通过抑制活性氧（ROS）生成和维持线粒体功能，保护神经元免受LPS诱导的神经炎症。
结论
T-006在LPS诱导的AD大鼠模型中通过抑制TLR4介导的MyD88/NF-κB信号通路来抑制神经炎症。
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