Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Shanghai Kai Bao Pharmaceutical CO. Ltd., Shanghai, 201401, China.
J Ethnopharmacol. 2020 Nov 15;262:112998. doi: 10.1016/j.jep.2020.112998. Epub 2020 May 30.
Natural bear bile powder (NBBP) has been used to treat seizures for thousands of years, but its application is greatly restricted due to ethical reasons. Cultured bear bile powder (CBBP), which is produced by biotransformation, may be an appropriate substitute for NBBP. However, the anti-convulsant effects of CBBP and its mechanisms remain unclear.
This study aimed to investigate the anti-convulsant effects and possible mechanisms of CBBP in a febrile seizure (FS) rat model.
FS was induced by placing the rats in a warm water bath (45.5 °C). The incidence rate and latency of FS, and hematoxylin-eosin staining (HE) were conducted for neurological damage. The levels of 4 bile acids and 8 main neurotransmitters in vivo were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The expression of bile acid related transports, neurotransmitter receptors, inflammatory factors, neurotrophic factors and glial fibrillary acidic protein (GFAP) in hippocampal tissues were detected by real-time PCR, western blotting, and immunohistochemistry.
Pre-treatments with CBBP and similarly, NBBP, significantly reduced the incidence rate and prolonged the latency of FS. Additionally, CBBP alleviated the histological injury induced by FS in the rat hippocampus tissue. LC-MS/MS analyses revealed that CBBP markedly increased the levels of tauroursodeoxycholic acid (TUDCA), taurochenodeoxycholic acid (TCDCA), ursodeoxycholic acid (UDCA), and chenodeoxycholic acid (CDCA) in FS rats. Furthermore, the content of gamma-aminobutyric acid (GABA) was up-regulated in rats pre-treated with CBBP whereas GFAP was down-regulated. CBBP also significantly suppressed the expression of interleukin -1β (IL-1β), tumor necrosis factor α (TNF-α), nuclear factor kappa B (NF-κB), and brain-derived neurotrophic factor (BDNF) and its TrkB receptors, and improved the expression of GABA type A receptors (GABAR) and farnesoid X receptors (FXR).
The present study demonstrated that CBBP had anti-convulsant effects in a FS rat model. CBBP may protect rats against FS, probably by up-regulating FXR, which was activated by increasing brain bile acids, up-regulating GABAergic transmission by inhibiting BDNF-TrkB signaling, and suppressing neuroinflammation by inhibiting the NF-κB pathway.
天然熊胆粉（NBBP）已被用于治疗癫痫已有数千年的历史，但由于伦理原因，其应用受到极大限制。通过生物转化生产的养殖熊胆粉（CBBP）可能是 NBBP 的合适替代品。然而，CBBP 的抗惊厥作用及其机制尚不清楚。
本研究旨在探讨 CBBP 在发热性惊厥（FS）大鼠模型中的抗惊厥作用及其可能机制。
通过将大鼠置于温水浴（45.5°C）中诱导 FS。进行 FS 发生率和潜伏期以及苏木精-伊红染色（HE）以评估神经损伤。通过液相色谱-串联质谱法（LC-MS/MS）在体内测量 4 种胆汁酸和 8 种主要神经递质的水平。通过实时 PCR、Western blot 和免疫组织化学检测海马组织中胆汁酸相关转运蛋白、神经递质受体、炎症因子、神经营养因子和胶质纤维酸性蛋白（GFAP）的表达。
CBBP 和类似地，NBBP 的预处理显著降低了 FS 的发生率并延长了潜伏期。此外，CBBP 减轻了 FS 诱导的大鼠海马组织的组织学损伤。LC-MS/MS 分析显示，CBBP 显著增加了 FS 大鼠中牛磺熊去氧胆酸（TUDCA）、牛磺鹅去氧胆酸（TCDCA）、熊去氧胆酸（UDCA）和鹅去氧胆酸（CDCA）的水平。此外，CBBP 预处理的大鼠中γ-氨基丁酸（GABA）的含量上调，而 GFAP 下调。CBBP 还显著抑制了白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）、核因子 kappa B（NF-κB）和脑源性神经营养因子（BDNF）及其 TrkB 受体的表达，并改善了 GABA 型 A 受体（GABAR）和法尼醇 X 受体（FXR）的表达。
本研究表明 CBBP 对 FS 大鼠模型具有抗惊厥作用。CBBP 可能通过上调 FXR 来保护大鼠免受 FS 的影响，FXR 可能通过增加脑胆汁酸激活，通过抑制 BDNF-TrkB 信号转导来上调 GABA 能传递，并通过抑制 NF-κB 途径来抑制神经炎症。
