The protective effects of neferine against paracetamol-induced liver injury are associated with the activation of SIRT1/Nrf2/HO-1 signaling pathway and inhibition of NF-kappa B/TNF-alpha/iNOS/COX-II cascade

Drug-induced hepatotoxicity is a significant public health issue that influences the development of novel pharmaceutical therapies and the retraction of numerous promising medications from the market. Therefore, the current study investigated the potential hepato-protective benefits of NEF against hepatotoxicity caused by paracetamol (APAP) in mice and assessed its underlying mechanisms. Mice were divided randomly into six groups; control (received normal saline), NEF control, APAP, N-acetylcysteine (NAC; served as a standard treatment) + APAP, NEF (10 mg/kg) + APAP, and NEF (20 mg/kg) + APAP. The serum and hepatic tissues were collected for different biochemical, genetic, and histological assessments. APAP induced profound hepatic damage that was evident through all biochemical, histological, and molecular assessments. NEF pretreatment opposed the elevation of liver injury biomarkers and attenuated hepatic histological disruption. At the molecular level, NEF increased the hepatic level and protein expression of SIRT-1. NEF increased the hepatic mRNA and protein expression of Nrf2 and HO-1. NEF also decreased hepatic level of oxidative stress biomarker, MDA and increased the hepatic levels of antioxidants: GSH, GR, GST, TAC, and SOD, NEF also counteracted the activation of NF-κB and inhibited the upregulation of different inflammatory cytokines as TNF-α and interleukins- (IL-1β and IL-6). Furthermore, NEF pretreatment decreased the hepatic level and mRNA expression of COX-II and iNOS. NEF ameliorated APAP-induced liver injury in mice where the higher dose of NEF (20 mg/kg) was more effective than the lower (10 mg/kg) compared to NAC. This effect is association with upregulation of SIRT-1/Nrf2/HO-1 and interruption of NF-κB/cytokines/iNOS/COX-II signaling cascades.