Cholinergic agonist Carbachol improves N-acetylcysteine treatment on Paracetamol-induced experimental hepatotoxicity in mice

Abstract A cholinomimetic agent carbachols (CCh) effect on mice model of paracetamol-induced hepatotoxicity was evaluated in comparison with antidote N-acetylcysteine (NAC). In the toxicity of paracetamol (APAP), production of N-acetyl-p-benzoquinone imine (NAPQI), which is a toxic metabolite of paracetamol for hepatocytes, increases. The antidote effect of NAC is due to its function as a precursor of GSH, which detoxifies the NAPQI. Studies have shown that the parasympathomimetics may contribute positively to paracetamol toxicity through many mechanisms. In this study, NAC, CCh, and NAC + CCh were administered intraperitoneally to mice with APAP toxicity. Mesenteric artery and portal vein blood flow were measured. AST, ALT, TNF-α, IL-1β, IL-6, IL-8, IL-10, IL-17 levels were measured and an increase was observed during APAP toxicity. The increases were mild relatively in the groups administered NAC, CCh, NAC + CCh. In this study, TAS, TOS, GSH, GSSG levels were also measured. After APAP toxicity, a decrease in antioxidant molecules, an increase in oxidant molecules, and oxidative stress index were observed. These findings were found to be less prominent in NAC, CCh, NAC + CCh administered groups. Results consistent with biochemical findings were obtained in histopathological evaluations. In conclusion, parasympathomimetic stimulation can be protective through reducing inflammation, activating antioxidant pathways in APAP-induced hepatotoxicity and may support NAC antidote therapy .