Experimental evaluation of high-dose L-ornithine L-aspartate in nonalcoholic steatohepatitis and its extrahepatic complications

Abstract

Introduction. In preclinical studies using models of nonalcoholic steatohepatitis (NASH), L-ornithine L-aspartate (LOLA) at 1.5 g/kg/day, a dose equivalent to the recommended human dose of 9 g/day, attenuated not only liver injury but also neuropsychiatric and skeletal muscle complications. The possibility of using higher LOLA doses may be of interest in the development of new approaches to the pharmacotherapy of NASH. Aim. To evaluate the effects of a twofold LOLA dose (3 g/kg/day) on liver injury and associated extrahepatic disorders in mice with experimental NASH. Materials and methods. Two-month-old male C57BL/6 mice were randomized into three groups: 1) Intact ( n = 20); 2) Control: diet- and toxin-induced NASH model ( n = 25); 3) LOLA: NASH model + LOLA administered via oral gavage at 3 g/kg once daily ( n = 25). After 3 months of NASH induction, blood ammonia and lactate, urinary urobilinogen and bilirubin were measured, and the Quick-Pytel functional test was performed. Animal behavior and cognitive function were assessed using the "Open field", "Light-dark box", "Spontaneous alternation in the T-maze", and "Novel object recognition" tests. Liver tissue was examined for the severity of inflammation, macrovesicular and microvesicular steatosis, necrosis, and fibrosis. Barrier function of the jejunum and colon was evaluated using the Ussing chamber. Results and discussion. Course administration of LOLA prevented the development of hyperammonemia ( p < 0.05) and bilirubinuria ( p < 0.01), ameliorated anxiety- and/or depression-like behavior ( p < 0.05, p < 0.01), and improved short-term recognition memory (p < 0.05) in mice. In the liver tissue of LOLA-treated mice, a significant reduction in necrosis severity was observed ( p < 0.05). LOLA administration also prevented the increase in jejunal epithelial permeability ( p < 0.05), but had no significant effect on the barrier function of the colon. Conclusion. The obtained data suggest potentially comparable efficacy of standard and twofold daily doses of LOLA in mice. The feasibility and safety of high-dose LOLA regimens require further evaluation in direct comparative studies.