Quercetin potentiates the hepatoprotective effect of sildenafil and/or pentoxifylline against intrahepatic cholestasis: Role of Nrf2/ARE, TLR4/NF-κB, and NLRP3/IL-1β signaling pathways

Intrahepatic cholestasis is a common pathological condition of several types of liver disorders. In this study, we aimed to investigate the regulatory effects of quercetin (QU) on selected phosphodiesterase inhibitors against alpha-naphthyl isothiocyanate (ANIT)-induced acute intrahepatic cholestasis. Cholestasis was induced in Wistar albino rats by ANIT as a single dose (60 mg/kg; P·O.). QU (50 mg/kg, daily, P·O.), sildenafil (Sild; 10 mg/kg, twice daily, P·O.), and pentoxifylline (PTX; 50 mg/kg, daily, P.O.) were evaluated either alone or in combinations for 10 days for their antioxidant, anti-inflammatory, and anti-pyroptotic effects. ANIT produced a prominent intrahepatic cholestasis as evidenced by a significant alteration in liver functions, histological structure, inflammatory response, and oxidative stress biomarkers. Furthermore, up-regulation of NF-κB-p65, TLR4, NLRP3, cleaved caspase-1, IKK-β, and IL-1β concurrently with down-regulation of Nrf-2, HO-1, and PPAR-γ expressions were observed after ANIT. QU, Sild, or PTX treatment significantly alleviated the disturbance induced by ANIT. These findings were further supported by the improvement in histopathological features. Additionally, co-administration of QU with Sild or PTX significantly improved liver defects due to ANIT as compared to the individual drugs. Combined QU with Sild or PTX exhibited promising hepatoprotective effects and anti-cholestatic properties through modulation of Nrf2/ARE, TLR4/NF- κB, and NLRP3/IL-1β signaling pathways.