Inhibition of mitochondrial respiratory chain in the brain of rats after hepatic failure induced by acetaminophen

Abstract

Hepatic encephalopathy is an important cause of morbidity and mortality in patients with severe hepatic failure. This disease is clinically characterized by a large variety of symptoms including motor symptoms, cognitive deficits, as well as changes in the level of alertness up to hepatic coma. Acetaminophen is frequently used in animals to produce an experimental model to study the mechanisms involved in the progression of hepatic disease. The brain is highly dependent on ATP and most cell energy is obtained through oxidative phosphorylation, a process requiring the action of various respiratory enzyme complexes located in a special structure of the inner mitochondrial membrane. In this context, the authors evaluated the activities of mitochondrial respiratory chain complexes in the brain of rats submitted to acute administration of acetaminophen and treated with the combination of N-acetylcysteine (NAC) plus deferoxamine (DFX) or taurine. These results showed that acetaminophen administration inhibited the activities of complexes I and IV in cerebral cortex and that the treatment with NAC plus DFX or taurine was not able to reverse this inhibition. The authors did not observe any effect of acetaminophen administration on complexes II and III activities in any of the structures studied. The participation of oxidative stress has been postulated in the hepatic encephalopathy and it is well known that the electron transport chain itself is vulnerable to damage by reactive oxygen species. Since there was no effect of NAC + DFX, the effect of acetaminophen was likely to be due to something else than oxidative stress.

Thioacetamide-Induced Fulminant Hepatic Failure Induces Cerebral Mitochondrial Dysfunction by Altering the Electron Transport Chain Complexes

“…Studies have reported a prevention of the mitochondrial respiratory complexes by administering with antioxidants in hepatic failure induced by acetaminophen and carbon tetra chloride [47,56]. In the current study, Treatment of the rats with antioxidants completely prevented the thioacetamide induced-inhibition of the electron transport chain complexes I and III suggesting that the oxidative stress is the critical factor leading to such inhibition.…”

“…Inhibition of Complex III has been reported to lead to the production of superoxide radicals [27]. Inhibition of mitochondrial electron transport chain complex I has been reported in different regions of the brain isolated from the acute liver failure caused by acetaminophen as well as carbon tetra chloride [47,56]. In addition studies of Rao et al, using congenital hyperammonemic sparse-fur mouse model indicated a reduced mitochondrial electron transport chain activities in various regions of the brain as well as in synaptic and non-synaptic mitochondria [57].…”

Pleurotus ostreatus opposes mitochondrial dysfunction and oxidative stress in acetaminophen-induced hepato-renal injury

“…The additional reactive metabolite depletes liver GSH and binds to proteins [ 46 , 47 ]. Toxic doses of APAP could cause changes in the morphology and function of liver mitochondria [ 48 , 49 ]. It was suggested that NAPQI binding to mitochondrial proteins leads to mitochondrial oxidative stress.…”

Acute Brain Damage Induced by Acetaminophen in Mice: Effect of Diphenyl Diselenide on Oxidative Stress and Mitochondrial Dysfunction

“…ATP depletion may occur in the brain mitochondria of APAPtreated mice. Further, aggravated by the induction of MPT in mitochondria, acute liver failure can cause accumulation of ammonia in the brain as demonstrated in a study of rat brains, (Panatto et al 2011) which found a decrease in complexes I and IV of respiratory chain. We believe that this effect on the mitochondrial respiratory chain can aggravate oxidative stress caused by APAP.…”