Aim of the study

Acute or chronic live failure could result in hyperammonemia and hepatic encephalopathy (HE). HE is a clinical complication characterized by severe cognitive dysfunction and coma. The ammonium ion (NH4+) is the most suspected toxic molecule involved in the pathogenesis of HE. NH4+ is a neurotoxic agent. Different mechanisms, including oxidative/nitrosative stress, inflammatory response, excitotoxicity, and mitochondrial impairment, are proposed for NH4+-induced neurotoxicity. N-acetyl cysteine (NAC) is a well-known thiol-reductant and antioxidant agent. Several investigations also mentioned the positive effects of NAC on mitochondrial function. In the current study, the effect of NAC treatment on brain mitochondrial indices and energy status was investigated in an animal model of HE.

Material and methods

Acetaminophen (APAP)-induced acute liver failure was induced by a single dose of the drug (800 mg/kg, i.p.) to C57BL/6J mice. Plasma and brain levels of NH4+ were measured. Then, brain mitochondria were isolated, and several indices, including mitochondrial depolarization, ATP level, lipid peroxidation, glutathione content, mitochondrial permeabilization, and dehydrogenase activity, were assessed.

Results

A significant increase in plasma and brain NH4+ was evident in APAP-treated animals. Moreover, mitochondrial indices of functionality were impaired, and mitochondrial oxidative stress biomarkers were significantly increased in APAP-treated mice. It was found that NAC treatment (100, 200, and 400 mg/kg, i.p.) significantly mitigated mitochondrial impairment in the brain of APAP-treated animals.

Conclusions

These data suggest the effects of NAC on brain mitochondrial function and energy status as a pivotal mechanism involved in its neuroprotective properties during HE.