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Modulation of the cannabinoid receptors by andrographolide attenuates hepatic apoptosis following bile duct ligation in rats with fibrosis

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Abstract

Bile acid-induced apoptosis plays an important role in the pathogenesis of cholestatic liver disease, and its prevention is of therapeutic interest. The aim of this study was to test whether the andrographolide limits the evolution of apoptosis in a murine model of bile duct ligation (BDL)-induced hepatic fibrosis. Male Sprague–Dawley rats were divided into four groups and hepatic apoptosis was induced by BDL for 2 weeks. The BDL animals were also treated with andrographolide (50, 100, and 200 mg/kg, i.p.) during the same time period. BDL-induced liver injury was associated with apoptosis and fibrosis, and the latter was significantly reduced in animals receiving andrographolide. The increase in serum alanine aminotransferase, asparate aminotransferase, tumor necrosis factor-α and IL-1β levels caused by BDL were also significantly reduced by treatment with andrographolide. Andrographolide decreased the intrahepatic protein levels of cannabinoid receptor 1 (CB1), Bax, and cytochrome c, along with of α-smooth muscle actin (α-SMA) and transforming growth factor-β (TGF-β), two markers of fibrogenesis. This effect was mediated by the inactivation of the c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK1/2) phosphorylation cascade, but it did not affect the p38 mitogen-activated protein kinase pathway. Additionally, andrographolide reduced the generation of hepatic lipid peroxidation and enhance senescence marker protein-30 levels to resist the hepatic oxidative stress in the presence of BDL. In conclusion, this study has identified AP as a potent protector against cholestasis-induced apoptosis in vivo. Its anti-apoptotic action largely relies on the inhibition of the oxidative stress pathway.

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Acknowledgments

This work was supported in part by grants from the National Science Council, Taipei, Taiwan, NSC97-2320-B-182-006-MY3 (H.H. Chang), and the research grant from the Chang Gung Memorial Hospital, CMRPD170111 (T.Y. Lee) and CMRPG 380811 (K.C. Lee).

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Authors and Affiliations

  1. Graduate Institute of Traditional Chinese Medicine, Chang Gung University, No. 259, Wen-Hwa 1st Road, Kwei-Shan Tao-Yuan, 333, Taiwan, ROC

    Tzung-Yan Lee & Hen-Hong Chang

  2. School of Traditional Chinese Medicine, Chang Gung University, Kwei-Shan Tao-Yuan, Taiwan, ROC

    Ko-Chen Lee

  3. Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Ko-Chen Lee & Hen-Hong Chang

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  1. Tzung-Yan Lee
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Correspondence to Hen-Hong Chang.

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Lee, TY., Lee, KC. & Chang, HH. Modulation of the cannabinoid receptors by andrographolide attenuates hepatic apoptosis following bile duct ligation in rats with fibrosis. Apoptosis 15, 904–914 (2010). https://doi.org/10.1007/s10495-010-0502-z

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