A low dose of naloxone mitigates autoimmune hepatitis by regulating TLR4/NF-κB and Nrf2/HO-1 signaling pathways

Abstract

Abstract Naloxone is a non-selective opiate receptor antagonist that is mainly used in the management of opiate addiction. Previously, naloxone has been shown to have anti-inflammatory and antioxidant properties. A popular and well-known animal model of autoimmune hepatitis that closely matches the pathogenic changes that take place in humans is the Concanavalin A (Con A) model. The present study demonstrates that a low dose of naloxone (LD NX) has the ability to improve hepatic function and attenuate hepatic damage induced by Con A as indicated by a substantial decrease in serum aminotransferase, bilirubin and enhancement of albumin production as well as liver pathological changes. Also, The proinflammatory cytokines, tumor necrosis factor-a (TNF-α), interferon- γ (IFN-γ), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were highly suppressed in animals pretreated with LD NX via interference with TLR4/NF-kB as well as JNK signaling pathways. Additionally, oxidative stress was significantly attenuated in animals pretreated with LD NX as indicated by high reduction in hepatic MDA and an increase in Nrf2, HO-1 expression and subsequent production of the endogenous antioxidants, SOD, CAT and GSH. Collectively, this study demonstrates that LD NX has the ability to mitigate Con A-induced autoimmune hepatitis via modulation of inflammatory cytokines secretion and interference with reactive oxygen species generation.