JKB-122 is effective, alone or in combination with prednisolone in Con A-induced hepatitis
JKB-122 is effective, alone or in combination with prednisolone in Con A-induced hepatitis
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DOI：
10.1016/j.ejphar.2017.07.012
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发表时间：
2017-10-05
影响因子：
5
通讯作者：
Chiu, Peter J. S.
中科院分区：
文献类型：
--
作者：
Hsu, Mei-Chi;Liu, Sheng-Hung;Chiu, Peter J. S.
Con - a诱导的小鼠肝炎是一种已建立的自身免疫性肝炎（AIH）模型。JKB-122是toll样受体4 （TLR4）拮抗剂，检测其肝保护活性。在Con A给药（15mg /kg i upsilon）的几个小时内，肝脏中促炎细胞因子的产生增加，并伴有炎症浸润。组织坏死的严重程度和循环肝酶的数量在Con A刺激后24 h达到峰值。JKB-122分别在Con A攻毒前24和16 h、同时、4和8 h （x 5剂）给药。在Con A攻毒后3、9和24 h采集血清和肝脏。JKB-122在Con A后24 h与对照相比，20和50 mg/kg po可分别抑制血清肝酶的升高47%和95%。JKB-122可显著抑制Con A诱导的肝脏病理病变，并可从Con A后3 h开始抑制ifn - γ IL-1 β、IL-4、IL-5、IL-6、IL- 17a和TNF-a的含量。此外，JKB-122与Con A同时（× 3剂量）也有类似的效果。最后，JKB-122增强了亚极大剂量强的松龙的治疗效果，改善了病变评分。由此可见，JKB-122在20和50 mg/kg po时对Con a诱导的小鼠肝炎肝酶升高有剂量依赖性的抑制作用，表明其具有肝保护作用。结果表明，JKB-122单独治疗或与强的松龙联合治疗可能是治疗AIH的可行方法。
Con A-induced hepatitis in mice is an established model of autoimmune hepatitis (AIH). JKB-122, a toll-like receptor 4 (TLR4) antagonist, was tested for hepatotprotectant activity. Within several hours of Con A challenge (15 mg/kg i upsilon), increased production of proinflammatory cytokines with inflammatory infiltrate occurred in the liver. The severity of tissue necrosis and the amount of circulating liver enzymes peak at 24 h post Con A challenge. JKB-122 was given 24 and 16 h before, then concurrently, and 4 and 8 h (x 5 doses) after challenge with Con A. Serum and liver were harvested at 3, 9 and 24 h post Con A challenge. JKB-122 at 20 and 50 mg/kg po prevented the increase of serum liver enzymes by 47% and 95% respectively vs vehicle control 24 h post Con A. JKB-122 significantly inhibited Con A-induced pathological lesions in the liver and the amount of IFN-gamma IL- 1 beta, IL-4, IL-5, IL-6, IL-17A and TNF-a starting as early as 3 h post Con A. Moreover, JKB-122 given concurrently (x 3 doses) with Con A showed similar effect. Finally, JKB-122 enhanced the therapeutic effects of submaximal dose of prednisolone with improved lesion score. It is concluded that JKB-122 at 20 and 50 mg/kg po caused dose-dependent inhibition of elevated liver enzymes in Con A-induced hepatitis in mice, indicating hepatoprotectant activity. The results suggest that JKB-122 as monotherapy or in combination with prednisolone may offer a viable approach to the treatment of AIH.