牛磺熊去氧胆酸可减少星形胶质细胞神经炎症，并缓解实验性自身免疫性脑脊髓炎小鼠的症状。

Taurochenodeoxycholic acid reduces astrocytic neuroinflammation and alleviates experimental autoimmune encephalomyelitis in mice.

机构信息

Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

出版信息

Immunobiology. 2023 May;228(3):152388. doi: 10.1016/j.imbio.2023.152388. Epub 2023 Apr 14.

DOI:10.1016/j.imbio.2023.152388

PMID:37079985

Abstract

OBJECTIVE

Multiple sclerosis (MS) is an immune regulatory disease that affects the central nervous system (CNS). The main pathological features include demyelination and neurodegeneration, and the pathogenesis is associated with astrocytic neuroinflammation. Taurochenodeoxycholic acid (TCDCA) is one of the conjugated bile acids in animal bile, and it is not clear whether TCDCA could improve MS by inhibiting the activation of astrocytes. This study was aimed to evaluate the effects of TCDCA on experimental autoimmune encephalomyelitis (EAE)-a classical animal model of MS, and to probe its mechanism from the aspect of suppressing astrocytic neuroinflammation. It is expected to prompt the potential application of TCDCA for the treatment of MS.

RESULTS

TCDCA effectively alleviated the progression of EAE and improved the impaired neurobehavior in mice. It mitigated the hyperactivation of astrocytes and down-regulated the mRNA expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 in the brain cortex. In the C6 astrocytic cell line induced by lipopolysaccharide (LPS), TCDCA treatment dose-dependently decreased the production of NO and the protein expression of iNOS and glial fibrillary acidic protein (GFAP). TCDCA consistently inhibited the mRNA expressions of COX2, iNOS and other inflammatory mediators. Furthermore, TCDCA decreased the protein expression of phosphorylated serine/threonine kinase (AKT), inhibitor of NFκB α (IκBα) and nuclear factor κB (NFκB). And TCDCA also inhibited the nuclear translocation of NFκB. Conversely, as an inhibitor of the G-protein coupled bile acid receptor Gpbar1 (TGR5), triamterene eliminated the effects of TCDCA in LPS-stimulated C6 cells.

CONCLUSION

TCDCA improves the progress of EAE by inhibiting the astrocytic neuroinflammation, which might be exerted by the regulation of TGR5 mediated AKT/NFκB signaling pathway. These findings may prompt the potential application of TCDCA for MS therapy by suppressing astrocyte inflammation.

摘要

目的

多发性硬化症（MS）是一种影响中枢神经系统（CNS）的免疫调节疾病。主要的病理特征包括脱髓鞘和神经退行性变，其发病机制与星形胶质细胞神经炎症有关。牛磺胆酸（TCDCA）是动物胆汁中的一种结合胆汁酸，目前尚不清楚 TCDCA 是否可以通过抑制星形胶质细胞的激活来改善 MS。本研究旨在评估 TCDCA 对实验性自身免疫性脑脊髓炎（EAE）的影响，这是一种 MS 的经典动物模型，并从抑制星形胶质细胞神经炎症的角度探讨其机制。这有望提示 TCDCA 治疗 MS 的潜在应用。

结果

TCDCA 可有效缓解 EAE 的进展并改善小鼠受损的神经行为。它减轻了星形胶质细胞的过度激活，并下调了大脑皮质中诱导型一氧化氮合酶（iNOS）、环氧化酶 2（COX2）、肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）的 mRNA 表达水平。在脂多糖（LPS）诱导的 C6 星形胶质细胞系中，TCDCA 处理呈剂量依赖性地降低了 NO 的产生和 iNOS 和胶质纤维酸性蛋白（GFAP）的蛋白表达。TCDCA 一致抑制了 COX2、iNOS 和其他炎症介质的 mRNA 表达。此外，TCDCA 降低了磷酸化丝氨酸/苏氨酸激酶（AKT）、NFκB α 抑制剂（IκBα）和核因子 κB（NFκB）的蛋白表达，并抑制了 NFκB 的核转位。相反，作为 G 蛋白偶联胆汁酸受体 Gpbar1（TGR5）的抑制剂，阿米洛利消除了 TCDCA 在 LPS 刺激的 C6 细胞中的作用。