Ammonia-induced mitochondrial impairment is intensified by manganese co-exposure: relevance to the management of subclinical hepatic encephalopathy and cirrhosis-associated brain injury.

AIM OF THE STUDY: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome ensuing from liver failure. The liver is the major site of ammonia detoxification in the human body. Hence, acute and chronic liver dysfunction can lead to hyperammonemia. Manganese (Mn) is a trace element incorporated in several physiological processes in the human body. Mn is excreted through bile. It has been found that cirrhosis is associated with hyperammonemia as well as body Mn accumulation. The brain is the primary target organ for both ammonia and Mn toxicity. On the other hand, brain mitochondria impairment is involved in the mechanism of Mn and ammonia neurotoxicity. MATERIAL AND METHODS: The current study was designed to evaluate the effect of Mn and ammonia and their combination on mitochondrial indices of functionality in isolated brain mitochondria. Isolated brain mitochondria were exposed to increasing concentrations of ammonia and Mn alone and/or in combination and several mitochondrial indices were assessed. RESULTS: The collapse of mitochondrial membrane potential, increased mitochondrial permeabilization, reactive oxygen species formation, and a significant decrease in mitochondrial dehydrogenase activity and ATP content were evident in Mn-exposed (0.005-1 mM) brain mitochondria. On the other hand, ammonia (0.005-0.5 mM) caused no significant changes in brain mitochondrial function. It was found that co-exposure of the brain mitochondria to Mn and ammonia causes more evident mitochondrial impairment in comparison with Mn and/or ammonia alone. CONCLUSIONS: These data indicate additive toxicity of ammonia and Mn in isolated brain mitochondria exposed to these neurotoxins.

Betaine treatment protects liver through regulating mitochondrial function and counteracting oxidative stress in acute and chronic animal models of hepatic injury.

Betaine is a derivative of the amino acid glycine widely investigated for its hepatoprotective properties against alcoholism. The protective properties of betaine in different other experimental models also have been documented. On the other hand, the exact cellular mechanism of cytoprotection provided by betaine is obscure. The current study was designed to evaluate the hepatoprotective effects of betaine and its potential mechanisms of hepatoprotection in two animal models of acute and chronic liver injury. Bile duct ligation (BDL) was used as a model of chronic liver injury and thioacetamide (TAA)-induced hepatotoxicity was applied as the acute liver injury model. Severe increase in serum markers of liver tissue damage along with significant liver tissue histopathological changes were evident in both acute and chronic models of hepatic injury. It was also found that tissue markers of oxidative stress were significantly increased in BDL and TAA-treated animals. Moreover, liver mitochondrial indices of functionality were deteriorated in both investigated models. Betaine supplementation (10 and 50 mg/kg, i.p) ameliorated hepatic injury as judged by decreased liver tissue histopathological alterations, a significant decrease in tissue markers of oxidative stress, and mitigation of serum biomarkers of hepatotoxicity. On the other hand, betaine (10 and 50 mg/kg, i.p) protected hepatocytes mitochondria in both chronic and acute models of hepatotoxicity. These data indicate that the antioxidative and mitochondria regulating properties of betaine could play a primary role in its mechanisms of hepatoprotection.