Inhibitory effects of armepavine against hepatic fibrosis in rats

<jats:title>Abstract</jats:title> <jats:p>Activation of hepatic stellate cells (HSCs) plays a crucial role in liver fibrogenesis. armepavine (Arm, C<jats:sub>19</jats:sub>H<jats:sub>23</jats:sub>O<jats:sub>3</jats:sub>N), an active compound from <jats:italic>Nelumbo nucifera</jats:italic>, 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 <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic>. A cell line of rat HSCs (HSC-T6) was stimulated with tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS) to evaluate the inhibitory effects of Arm. An <jats:italic>in vivo</jats:italic> 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. <jats:italic>In vitro</jats:italic>, Arm (1-10 μM) concentration-dependently attenuated TNF-α- and LPS-stimulated α-SMA protein expression and AP-1 activation by HSC-T6 cells without adverse cytotoxicity. Arm also suppressed TNF-α-induced collagen collagen deposition, NFκB activation and MAPK (p38, ERK1/2, and JNK) phosphorylations. <jats:italic>In vivo</jats:italic>, Arm treatment significantly reduced plasma AST and ALT levels, hepatic α-SMA expression and collagen contents, and fibrosis scores of BDL rats as compared with vehicle treatment. Moreover, Arm attenuated the mRNA expression levels of <jats:italic>col 1α2, TGF-β1</jats:italic>, <jats:italic>TIMP-1, ICAM-1</jats:italic>, <jats:italic>iNOS</jats:italic>, and <jats:italic>IL-6</jats:italic> genes, but up-regulated <jats:italic>metallothionein</jats:italic> genes. Our study results showed that Arm exerted both <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> antifibrotic effects in rats, possibly through anti-NF-κB activation pathways.</jats:p>