The effect of cholinesterase inhibition on liver dysfunction in experimental acute liver failure: a randomized controlled study

Introduction Acute liver failure (ALF), similar to sepsis, is associated with an overwhelming activation of the immune response in which hepatic and circulating inflammatory cytokines play a pivotal role. The cholinesterase inhibitor neostigmine has been shown to have anti-inflammatory properties in experimental sepsis. We investigated the role of neostigmine in attenuating D-galactosamine (D-GalN)-induced ALF. Materials and methods Thirty-six female Wistar rats were randomly allocated to three groups: the control group, the D-GalN group receiving a single intraperitoneal injection of D-GalN (400 mg/kg body weight), and the neostigmine-treated D-GalN group receiving a single intraperitoneal injection of D-GalN followed 24 h later by intraperitoneal injection of neostigmine methylsulfate 0.25% (80 μg/kg body weight) three times daily for 3 successive days. Rats were killed 24 h after the last injection. Plasma levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total proteins, albumin, prothrombin, total bilirubin, and hepatic levels of superoxide dismutase and malondialdehyde were measured. Liver expression of cytokines ( HMGB-1, TNF-α, and IL-10) and histopathology were evaluated. Results Neostigmine attenuated liver dysfunction and improved liver synthetic and excretory functions. It reduced proinflammatory cytokine HMGB-1 [95% confidence interval (CI) 0.33–1.09] and TNF-α (95% CI 1.26–2.06) expression compared with the D-GalN group (95% CI 2.67–4.73 and 7.33–14.53, respectively, P 0.001) and increased expression of the anti-inflammatory cytokine IL-10 in the liver tissue (95% CI 2.49–4.17 vs. 0.04–0.21 in the D-GalN group, P 0.001). Neostigmine also significantly increased antioxidant level and decreased oxidative burden caused by D-GalN. Conclusion Neostigmine improved liver function in a rat ALF model through an anti-inflammatory activity.