Conophylline suppresses hepatic stellate cells and attenuates thioacetamide-induced liver fibrosis in rats

Background & Aims: Conophylline (CnP) is a vinca alkaloid purified from a tropical plant and inhibits activation of pancreatic stellate cells. We investigated the effect of CnP on hepatic stellate cells (HSC) in vitro. We also examined whether CnP attenuates hepatic fibrosis in vivo. Method: We examined the effect of CnP on the expression of alpha-smooth muscle actin (alpha-SMA) and collagen-1, DNA synthesis and apoptosis in rat HSC and Lx-2 cells. We also examined the effect of CnP on hepatic fibrosis induced by thioacetamide (TAA). Results: In rat HSC and Lx-2 cells, CnP reduced the expression of a-SMA and collagen-1. CnP inhibited DNA synthesis induced by serum. CnP also promoted activation of caspase-3 and induced apoptosis as assessed by DNA ladder formation and TUNEL assay. In contrast, CnP did not induce apoptosis in AML12 cells. We then examined the effect of CnP on TAA-induced cirrhosis. In TAA-treated rats, the surface of the liver was irregular and multiple nodules were observed. Histologically, formation of pseudolobules surrounded by massive fibrous tissues was observed. When CnP was administered together with TAA, the surface of the liver was smooth and liver fibrosis was markedly inhibited. Collagen content was significantly reduced in CnP-treated liver. Conclusion: Conophylline suppresses HSC and induces apoptosis in vitro. CnP also attenuates formation of the liver fibrosis induced by TAA in vivo.