Department of Pharmacology, Medical School of Ningbo University, Ningbo, Zhejiang 315211, P.R. China.
Department of Basic Nutrition, Ningbo College of Health Sciences, Ningbo, Zhejiang 315100, P.R. China.
Int J Mol Med. 2020 Dec;46(6):2271-2279. doi: 10.3892/ijmm.2020.4742. Epub 2020 Sep 29.
SP600125 is a classic inhibitor of c‑Jun‑N‑terminal kinase (JNK) that is widely used in numerous medicinal studies, but its administration regimen has yet to be optimized. In the present study, intraperitoneal (i.p.) and intragastric (i.g.) injections of 15 mg/kg SP600125 was performed in mice to compare the inhibitory effect against JNK signalling in cholestasis induced by α‑naphthylisothiocyanate (ANIT). SP600125 at a dose of 15 mg/kg administered by i.p. substantially decreased ANIT‑induced liver injury as observed by biochemical and histopathological examinations. The adaptation of bile acid synthesis was inhibited in the A‑SP‑i.p. group compared with that in the A‑SP‑i.g. group, as indicated by the expression analysis of CYP7A1 and CYP8B1. The transcription of the pro‑inflammatory factors IL‑6, IL‑1β, ICAM‑1 and IL‑10 supported the differential toxic responses. Western blot analysis revealed that JNK signalling activated by ANIT was inhibited more markedly in the A‑SP‑i.p. group than in the A‑SP‑i.g. group. The peak concentration and the AUC0‑24 of SP600125 in the A‑SP‑i.p. group were 5‑fold and 1.56‑fold higher, respectively, compared with those in the A‑SP‑i.g. group. These data indicated that i.p. administration of SP600125 produced a high plasma exposure profile, which directly determined its efficacy of blocking the JNK signalling. This effect of SP600125 on the JNK pathway may provide an optimized design for future in vivo investigations.
SP600125 是一种经典的 c-Jun-N-末端激酶（JNK）抑制剂，广泛应用于许多医学研究中，但它的给药方案尚未得到优化。在本研究中，通过腹腔内（i.p.）和胃内（i.g.）注射 15mg/kg SP600125，比较了其对α-萘基异硫氰酸酯（ANIT）诱导的胆汁淤积中 JNK 信号的抑制作用。腹腔内注射 15mg/kg SP600125 可显著降低生化和组织病理学检查观察到的 ANIT 诱导的肝损伤。与 A-SP-i.g. 组相比，A-SP-i.p. 组胆汁酸合成的适应性受到抑制，这表现在 CYP7A1 和 CYP8B1 的表达分析上。促炎因子 IL-6、IL-1β、ICAM-1 和 IL-10 的转录支持了不同的毒性反应。Western blot 分析表明，ANIT 激活的 JNK 信号在 A-SP-i.p. 组中的抑制作用比 A-SP-i.g. 组更为明显。A-SP-i.p. 组中 SP600125 的峰浓度和 AUC0-24 分别比 A-SP-i.g. 组高 5 倍和 1.56 倍。这些数据表明，SP600125 的腹腔内给药产生了较高的血浆暴露谱，这直接决定了其阻断 JNK 信号的疗效。SP600125 对 JNK 通路的这种作用可能为未来的体内研究提供优化设计。
