Phosphodiestrase‐1 and 4 inhibitors ameliorate liver fibrosis in rats: Modulation of cAMP/CREB/TLR4 inflammatory and fibrogenic pathways

Abstract

Background: Phosphodiestrase (PDE) enzymes are suggested to play a leading role in fibrogenesis of liver where studies showed the possible implication of PDE 1 & 4 in liver injury proposing them as possible targets for treating liver fibrosis. Aim: The present study was designed to investigate, for the first time, the possible therapeutic effects of selective inhibitors of PDE‐1 (vinpocetine) and PDE‐4 (roflumilast) in liver fibrosis induced by diethylnitrosamine (DEN) in rats. Main methods: Rats were given DEN (100 mg/kg, i.p.) once weekly for 6 weeks to induce liver fibrosis. Vinpocetine (10 mg/kg/day) or roflumilast (0.5 mg/kg/day) was then orally administered for 2 weeks. Key findings: Vinpocetine significantly suppressed the contents of hydroxyproline, transforming growth factor‐beta 1 (TGF‐&bgr;1), nuclear factor‐kappa B (NF‐&kgr;B) whereas roflumilast normalized them. Moreover, tumor necrosis factor‐alpha (TNF‐&agr;) content and protein expressions of toll‐like receptor 4 (TLR4) and tissue inhibitor of metalloproteinase‐1 (TIMP‐1) were markedly decreased whereas cAMP response element binding (CREB) protein expression was significantly elevated by both treatments. Additionally, vinpocetine and roflumilast up‐regulated the gene expression of bone morphogenetic protein and activin membrane‐bound inhibitor (BAMBI) receptor where roflumilast showed better results. PDE1 and 4 activities were inhibited by vinpocetine and roflumilast, respectively. The superior results offered by roflumilast could be related to the higher cAMP level obtained relative to vinpocetine. Significance: Our study manifested the up‐regulation of PDE enzymes (1 & 4) in liver fibrosis and addressed the therapeutic role of vinpocetine and roflumilast as PDEIs through a cAMP‐mediated TLR4 inflammatory and fibrogenic signaling pathways. Graphical abstract: Figure. No caption available.