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 201203, China.
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 201203, China.
Chin J Nat Med. 2023 Sep;21(9):710-720. doi: 10.1016/S1875-5364(23)60449-2.
Parkinson's disease (PD) is a common neurodegenerative disease in middle-aged and elderly people. In particular, increasing evidence has showed that astrocyte-mediated neuroinflammation is involved in the pathogenesis of PD. As a precious traditional Chinese medicine, bear bile powder (BBP) has a long history of use in clinical practice. It has numerous activities, such as clearing heat, calming the liver wind and anti-inflammation, and also exhibits good therapeutic effect on convulsive epilepsy. However, whether BBP can prevent the development of PD has not been elucidated. Hence, this study was designed to explore the effect and mechanism of BBP on suppressing astrocyte-mediated neuroinflammation in a mouse model of PD. PD-like behavior was induced in the mice by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30 mg·kg) for five days, followed by BBP (50, 100, and 200 mg·kg) treatment daily for ten days. LPS stimulated rat C6 astrocytic cells were used as a cell model of neuroinflammation. THe results indicated that BBP treatment significantly ameliorated dyskinesia, increased the levels of tyrosine hydroxylase (TH) and inhibited astrocyte hyperactivation in the substantia nigra (SN) of PD mice. Furthermore, BBP decreased the protein levels of glial fibrillary acidic protein (GFAP), cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS), and up-regulated the protein levels of takeda G protein-coupled receptor 5 (TGR5) in the SN. Moreover, BBP significantly activated TGR5 in a dose-dependent manner, and decreased the protein levels of GFAP, iNOS and COX2, as well as the mRNA levels of GFAP, iNOS, COX2, interleukin (IL) -1β, IL-6 and tumor necrosis factor-α (TNF-α) in LPS-stimulated C6 cells. Notably, BBP suppressed the phosphorylation of protein kinase B (AKT), inhibitor of NF-κB (IκBα) and nuclear factor-κB (NF-κB) proteins in vivo and in vitro. We also observed that TGR5 inhibitor triamterene attenuated the anti-neuroinflammatory effect of BBP on LPS-stimulated C6 cells. Taken together, BBP alleviates the progression of PD mice by suppressing astrocyte-mediated inflammation via TGR5.
帕金森病（PD）是一种常见的中老年神经退行性疾病。特别是，越来越多的证据表明，星形胶质细胞介导的神经炎症参与了 PD 的发病机制。熊胆粉（BBP）作为一种珍贵的中药，在临床实践中已有悠久的应用历史。它具有清热、平肝息风、抗炎等多种活性，对惊厥性癫痫也有较好的治疗作用。然而，BBP 是否能预防 PD 的发生尚未阐明。因此，本研究旨在探讨 BBP 抑制 PD 小鼠模型中星形胶质细胞介导的神经炎症的作用及其机制。通过腹腔注射 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）（30mg·kg）连续 5 天诱导 PD 样行为，随后每日给予 BBP（50、100 和 200mg·kg）治疗 10 天。LPS 刺激的大鼠 C6 星形胶质细胞被用作神经炎症的细胞模型。结果表明，BBP 治疗显著改善了运动障碍，增加了黑质（SN）中酪氨酸羟化酶（TH）的水平，并抑制了 PD 小鼠中星形胶质细胞的过度激活。此外，BBP 降低了 SN 中神经胶质纤维酸性蛋白（GFAP）、环氧化酶 2（COX2）和诱导型一氧化氮合酶（iNOS）的蛋白水平，并上调了 SN 中的 Takeda G 蛋白偶联受体 5（TGR5）的蛋白水平。此外，BBP 以剂量依赖性方式显著激活 TGR5，并降低 LPS 刺激的 C6 细胞中 GFAP、iNOS 和 COX2 的蛋白水平以及 GFAP、iNOS、COX2、白细胞介素（IL）-1β、IL-6 和肿瘤坏死因子-α（TNF-α）的 mRNA 水平。值得注意的是，BBP 抑制了体内和体外蛋白激酶 B（AKT）、核因子-κB（NF-κB）抑制物（IκBα）和 NF-κB 蛋白的磷酸化。我们还观察到，TGR5 抑制剂三甲噻嗪减弱了 BBP 对 LPS 刺激的 C6 细胞的抗炎作用。综上所述，BBP 通过抑制 TGR5 抑制星形胶质细胞介导的炎症来减轻 PD 小鼠的进展。
