Role of Nrf2/HO-1 and PI3K/Akt Genes in the Hepatoprotective Effect of Cilostazol

摘要

Background: Cilostazol, a phosphodiesterase 3 inhibitor (PDE3I), is a platelet aggregationinhibitor and vasodilator that is useful for treating intermittent claudication. Experimental studieshave shown that cilostazol has potent anti-inflammatory, anti-oxidant effects effects.Objectives: Although the hepatoprotective effect cilostazol has been studied, the molecular mechanismsof such protection, including: the nuclear factor-erythroid 2-related factor 2 (Nrf2) / hemoxygenase(HO-1) and the phosphoinositide 3-kinase (PI3K) /serine/threonine kinase (Akt) pathwaysare not fully explored, which is the aim of this study.Methods: To achieve the aim of this study, 35 rats were grouped into: control groups, liver injurygroup (model- non treated: injected with thioacetamide (TAA), 150 mg/kg, i.p.), and two cilostazoltreatedgroups (treated with cilostazol 10 and 50 mg/kg, p.o.). The rats were treated for 8 days andinjected with TAA on the 7th day of the experiment and sacrificed 48 hours after TAA injection.Results: The model group showed evidence of liver injury as indicated by the elevation of liverenzymes and confirmed by histopathological findings. TAA-induced liver injury was accompaniedby down-regulation of the cytoprotective pathways: PI3K/Akt and Nrf2/HO-1 mRNAs. Cilostazoladministration ameliorated TAA-induced liver injury, where it caused a significant improvement inthe activity of liver enzymes as well as in the histopathological changes. Such an effect was associatedwith a significant increase in the expression of PI3K/Akt and Nrf2/HO-1 mRNAs as detectedby Real-time reverse transcription polymerase chain reaction (RT-PCR).Conclusion: Cilostazol protected rats against TAA hepatotoxicity through up-regulation ofPI3K/Akt and Nrf2/HO-1 gene expression.