Inhibitory effects of armepavine against hepatic fibrosis in rats.

Abstract

Activation of hepatic stellate cells (HSCs) plays a crucial role in liver fibrogenesis. armepavine (Arm, C19H23O3N), an active compound from Nelumbo nucifera, has been shown to exert immunosuppressive effects on T lymphocytes and on lupus nephritic mice. The aim of this study was to investigate whether Arm could exert anti-hepatic fibrogenic effects in vitro and in vivo. A cell line of rat HSCs (HSC-T6) was stimulated with tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) to evaluate the inhibitory effects of Arm. An in vivo therapeutic study was conducted in bile duct-ligated (BDL) rats. BDL rats were given Arm (3 or 10 mg/kg) by gavage twice daily for 3 weeks starting from the onset of BDL. Liver sections were taken for fibrosis scoring, immuno-fluorescence staining and quantitative real-time mRNA measurements. In vitro, Arm (1-10 microM) concentration-dependently attenuated TNF-alpha- and LPS-stimulated alpha-SMA protein expression and AP-1 activation by HSC-T6 cells without adverse cytotoxicity. Arm also suppressed TNF-alpha-induced collagen collagen deposition, NFkappaB activation and MAPK (p38, ERK1/2, and JNK) phosphorylations. In vivo, Arm treatment significantly reduced plasma AST and ALT levels, hepatic alpha-SMA expression and collagen contents, and fibrosis scores of BDL rats as compared with vehicle treatment. Moreover, Arm attenuated the mRNA expression levels of col 1alpha2, TGF-beta1, TIMP-1, ICAM-1, iNOS, and IL-6 genes, but up-regulated metallothionein genes. Our study results showed that Arm exerted both in vitro and in vivo antifibrotic effects in rats, possibly through anti-NF-kappaB activation pathways.

• Authors: Ting-Chun Weng, Chien-Chang Shen, Yung-Tsung Chiu, Yun-Lian Lin, Cheng-Deng Kuo, Yi-Tsau Huang
• Journal: Journal of biomedical science (J Biomed Sci) Vol. 16 Pg. 78 (Sep 02 2009) ISSN: 1423-0127 [Electronic] England
• PMID: 19723340 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Anti-Inflammatory Agents, Non-Steroidal
• Benzylisoquinolines
• Immunosuppressive Agents
• Lipopolysaccharides
• NF-kappa B
• RNA, Messenger
• Tumor Necrosis Factor-alpha
• Collagen
• armepavine

Topics

• Actins (biosynthesis)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use, toxicity)
• Benzylisoquinolines (pharmacology, therapeutic use, toxicity)
• Cell Line (drug effects, ultrastructure)
• Collagen (biosynthesis)
• Drug Evaluation, Preclinical
• Gene Expression Regulation (drug effects)
• Hepatic Stellate Cells (drug effects, ultrastructure)
• Immunosuppressive Agents (pharmacology, therapeutic use, toxicity)
• Lipopolysaccharides (pharmacology)
• Liver Cirrhosis, Biliary (blood, drug therapy, genetics, pathology)
• Liver Cirrhosis, Experimental (blood, drug therapy, genetics, pathology)
• MAP Kinase Signaling System (drug effects)
• Male
• NF-kappa B (metabolism)
• Nelumbo (chemistry)
• Phosphorylation
• Phytotherapy
• Protein Processing, Post-Translational (drug effects)
• RNA, Messenger (biosynthesis, genetics)
• Rats
• Rats, Sprague-Dawley
• Tumor Necrosis Factor-alpha (pharmacology)