Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drug Research/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou 510632, China.
State Key Laboratory of Critical Technology in Innovative Chinese Medicine, Tasly Pharmaceutical Group Co., Ltd., Tianjin 300410, China; Tasly Pharmaceutical Group Co., Ltd., Tianjin 300410, China.
J Pharm Biomed Anal. 2023 Apr 1;227:115271. doi: 10.1016/j.jpba.2023.115271. Epub 2023 Jan 25.
Jitongning tablet (JTNT) is a Traditional Chinese Medicine (TCM) prescription used for the treatment of Ankylosing spondylitis (AS). Currently, it is in phase II clinical trial (NCT03932019) for patients with active axial Spondyloarthritis (axSpA), showing great promise for the treatment of AS. However, the potential material basis and the underlying mechanisms for JTNT to treat AS remain elusive. Here, we performed UPLC-Q-TOF-MS to determine the in vivo metabolic profile of JTNT in rats and conducted in vivo studies including acetic acid-induced writhing, hot plate models, and collagen-induced arthritis (CIA) in rats to evaluate and validate the analgesic and anti-inflammatory effects of JTNT, two main symptoms for AS. Additionally, network pharmacology combined with molecular docking was performed to investigate the potential underlying mechanisms. As a result, a total of 116 xenobiotics were identified from the plasma, urine, and brain tissues of rats after oral administration of JTN extracts. Pharmacological evaluation revealed that fractions JTN-3 and JTN-4 exerted significant analgesic activities by reducing the number of writhes in an acetic acid-induced writhing mice model. JTN extract also exerted excellent therapeutic effects in the CIA model by ameliorating paw edema and decreasing systemic manifestation of inflammation and the level of circulating immune complex (CIC) and interferon γ (IFN-γ). Fractions of JTN extract, especially JTN-2 and JTN-4, on the other hand, ameliorated the secondary lesions caused by chicken type II collagen (CII) to a certain extent. Further, network pharmacology combined with molecular docking suggested crucial roles of inflammation and immune-related genes such as MAPK1, MAPK14, NOS3, and RELA in the treatment of AS by JTNT. In conclusion, our studies suggest that the isoquinoline and diterpenoid alkaloids from Corydalis Rhizoma and Aconiti Radix Cocta, along with coumarins from Angelicae Pubescentis Radix, may be the main bioactive components, and the AS treatment mechanism may mainly involve immune regulation of JTNT. These results help clarify the potential material basis and underlying mechanisms of JTNT for the treatment of AS, facilitating the broad application of this TCM in clinical practice.
脊痛宁胶囊（JTNT）是一种用于治疗强直性脊柱炎（AS）的中药方剂。目前，它正在进行治疗活动性轴性脊柱关节炎（axSpA）患者的 II 期临床试验（NCT03932019），显示出对 AS 治疗的巨大潜力。然而，JTNT 治疗 AS 的潜在物质基础和潜在机制仍不清楚。在这里，我们使用 UPLC-Q-TOF-MS 来确定 JTNT 在大鼠体内的代谢谱，并进行体内研究，包括乙酸诱导的扭体、热板模型和胶原诱导性关节炎（CIA），以评估和验证 JTNT 的镇痛和抗炎作用，这是 AS 的两个主要症状。此外，还进行了网络药理学结合分子对接研究，以探讨潜在的潜在机制。结果，从大鼠口服 JTNT 提取物后的血浆、尿液和脑组织中鉴定出了总共 116 种外源性物质。药效学评价表明，JTN-3 和 JTN-4 两个馏分通过减少醋酸诱导的扭体模型中小鼠扭体的数量表现出显著的镇痛活性。JTN 提取物在 CIA 模型中也表现出优异的治疗效果，通过改善爪肿胀和降低全身性炎症和循环免疫复合物（CIC）和干扰素γ（IFN-γ）水平。另一方面，JTN 提取物的馏分，特别是 JTN-2 和 JTN-4，在一定程度上改善了鸡 II 型胶原（CII）引起的继发性病变。此外，网络药理学结合分子对接表明，MAPK1、MAPK14、NOS3 和 RELA 等炎症和免疫相关基因在 JTNT 治疗 AS 中的关键作用。总之，我们的研究表明，延胡索和乌头中的异喹啉和二萜生物碱，以及当归中的香豆素，可能是主要的生物活性成分，JTNT 的治疗机制可能主要涉及免疫调节。这些结果有助于阐明 JTNT 治疗 AS 的潜在物质基础和潜在机制，促进该中药在临床实践中的广泛应用。
