Anti-neuroinflammatory and Neuroprotective Effects of T-006 on Alzheimer's Disease Models by Modulating TLR4-Mediated MyD88/ NF-κB Signaling.

CNS & neurological disorders drug targets Pub Date : 2025-01-08 DOI:10.2174/0118715273337232241121113048

Haiyun Chen, Xiao Chang, Jiemei Zhou, Guiliang Zhang, Jiehong Cheng, Zaijun Zhang, Jieyu Xing, Chunyan Yan, Zheng Liu

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Abstract

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.

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T-006通过调节tlr4介导的MyD88/ 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

由小胶质细胞激活引起的神经炎症被认为是阿尔茨海默病（AD）的重要致病因素。在AD转基因小鼠模型中，四甲基吡嗪衍生物T-006通过抑制tau蛋白表达和磷酸化来减轻认知缺陷。近年来，研究证实T-006能显著降低APP/PS1小鼠的总β淀粉样蛋白（Aβ）肽和胶质纤维酸性蛋白（GFAP）水平，并抑制离子钙结合受体分子-1 （Iba-1）的表达。因此，我们进一步研究了T-006对ad样病理神经炎症的影响。方法：观察T-006对脂多糖（LPS）诱导的AD大鼠的抗炎作用及其机制。还测量了对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/星形胶质细胞活化，显著改善脂多糖诱导的AD大鼠认知功能障碍。进一步的细胞实验发现，T-006以浓度依赖的方式显著保留了lps诱导的BV2小胶质细胞中炎症因子的异常升高，而单独使用T-006对正常培养的细胞没有影响。T-006还能降低LPS刺激下BV2细胞中toll样受体4 (TLR4)/髓样分化蛋白88 (MyD88)/NF-κB信号相关蛋白的水平。TAK242选择性抑制TLR4，在lps处理的BV2细胞中，T-006的作用略有减弱，但无显著性。重要的是，T-006通过抑制活性氧（ROS）的产生和维持线粒体功能来保护神经元免受lps诱导的神经炎症。结论：T-006抑制tlr4介导的MyD88/NF-κB信号通路，抑制lps诱导的AD大鼠神经炎症。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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CNS & neurological disorders drug targets

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