Carnosine protects brain mitochondria under hyperammonemic conditions: Relevance to hepatic encephalopathy treatment

Abstract

Elevated brain ammonia in hepatic encephalopathy (HE) is a serious and potentially fatal complication. Ammonia-induced oxidative stress, mitochondrial dysfunction, and energy crisis are known as the major mechanisms of ammonia-induced brain injury. Hence, targeting mitochondria seems to be a therapeutic point of intervention in the treatment of HE. Carnosine is abundantly found in human body. Several biological functions including the mitochondrial protective properties are attributed to this peptide. The current investigation was designed to evaluate the effect of carnosine on brain mitochondria exposed to toxic ammonia concentrations. Isolated brain mitochondria were exposed to ammonia (5 and 10mM). It was found that ammonia inhibited mitochondrial dehydrogenases activity (MTT test), caused mitochondrial membrane potential (MMP) collapse, induced mitochondrial swelling (MPP), and increased reactive oxygen species (ROS) in isolated brain mitochondria. Furthermore, a significant amount of lipid peroxidation (LPO), along with glutathione (GSH) and ATP depletion were detected in ammonia-treated mitochondria. It was found that carnosine (1, 5, 10 and 20mM) alleviated ammonia-induced mitochondrial dysfunction. The current investigation demonstrates that carnosine preserved brain mitochondrial function in a hyperammonemic environment. The data suggest this peptide as a potential protective agent with therapeutic capability against hyperammonemia-induced energy metabolism failure and brain injury.