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

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 (NH4 Cl), L-CA or a mixture of NH4 Cl, 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 NH4 Cl. In contrast, co-treatment with L-CA significantly inhibited the cytotoxic effects of NH4 Cl. The intracellular levels of almost all AAs involving glutamine and branched-chain AAs (BCAAs) were significantly increased in the NH4 Cl-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 NH4 Cl-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.