L‐carnitine prevents ammonia‐induced cytotoxicity and disturbances in intracellular amino acid levels in human astrocytes

Abstract

Background and Aim L‐carnitine (L‐CA) has been used therapeutically to treat hepatic encephalopathy with hyperammonemia, but the mechanism by which L‐CA contributes to ammonia detoxification in the brain is still unclear. Thus, the cytotoxicity and changes in intracellular amino acids (AAs) in astrocytes with hyperammonemia following L‐CA administration were studied. Methods Human astrocytes were treated with ammonium chloride (NH4Cl), L‐CA or a mixture of NH4Cl, and L‐CA under defined conditions. Total intracellular reactive oxygen species and lactate dehydrogenase leakage were measured following different treatment periods. The intracellular levels of AAs in astrocytes were determined using metabolomic analysis. Results Intracellular total reactive oxygen species and lactate dehydrogenase leakage were significantly increased after treatment with NH4Cl. In contrast, co‐treatment with L‐CA significantly inhibited the cytotoxic effects of NH4Cl. The intracellular levels of almost all AAs involving glutamine and branched‐chain AAs (BCAAs) were significantly increased in the NH4Cl‐treated cells compared with in the control cells; these changes in BCAA levels were reduced with L‐CA co‐treatment. Additionally, the level of 3‐methyl‐2‐oxovaleric acid, which is a metabolite from isoleucine and plays a critical role in neurological damage, was significantly increased in the NH4Cl‐treated cells, but this metabolite was significantly decreased with L‐CA co‐treatment. Conclusion L‐CA protects human astrocytes from ammonia‐induced acute cytotoxic effects and the increased intracellular levels of glutamine and BCAAs.

1H NMR-Based Metabolic Signatures in the Liver and Brain in a Rat Model of Hepatic Encephalopathy

“…8 Wang et al observed increase in glutamine and branched chain amino acids (BCAAs) in human astrocytes treated with ammonium chloride. 9 The role of cerebral energy deficits in the development of HE has been shown in terms of activation of cerebral AMP-activated protein kinase, a major energy sensor in the cell, as a compensatory response to liver failure following bile duct ligation, BDL. 10 Furthermore, several studies have examined disturbances in energy metabolism in HE either in patients 11 or in animal models of HE and findings are incoherent.…”

Impaired brain function improved by l-carnitine in patients with cirrhosis: evaluation using near-infrared spectroscopy

“…Recently Wang et al 56 reported that intracellular reactive oxygen species and all amino acids, including glutamine, were increased in the NH 4 Cl-treated human astrocyte; however, these reactions were reduced with l-carnitine treatment. Moreover, in the NH 4 Cl-treated human astrocytes, increased concentration of 3-methyl-2-oxovaleric acid, which was ammonia induced and played a crucial role in neurological impairment, was significantly decreased with l-carnitine co-treatment.…”

l‐Carnitine protects against 1,4‐benzoquinone‐induced apoptosis and DNA damage by suppressing oxidative stress and promoting fatty acid oxidation in K562 cells

“…Studies have demonstrated that LC exerts beneficial effects primarily through its antioxidant and free‐radical scavenging properties 32‐34 . Wang et al exposed human astrocytes to ammonium chloride with or without LC and showed that LC cotreatment significantly inhibited increasing ROS levels and lactate dehydrogenase leakage 35 . Another recent study revealed that antioxidant therapy with LC reduced oxidative DNA damage and lipid peroxidation in patients with 3‐hydroxy‐3‐methylglutaric aciduria 36 .…”