Datsko V. Experimental study of the protective effect of L-ornithine L-aspartate in liver damage of various origins

Українська версія

Thesis for the degree of Doctor of Philosophy (PhD)

State registration number

0823U100402

Applicant for

Specialization

  • 222 - Медицина

20-06-2023

Specialized Academic Board

ДФ 58.601.080

Ternopil National Medical University named after I. Gorbachevsky of the Ministry of Health of Ukraine

Essay

The dissertation provides scientific justification and presents the results of addressing the urgent task of clarifying the effectiveness of L-ornithine L-aspartate (LOLA) in acute hepatitis and liver cirrhosis, as well as establishing the nitrogen oxide and polyamine-dependent mechanisms of the drug's action. It was established that that the protective action of LOLA in hepatitis and cirrhosis has a complex and multifaceted mechanism that is associated with the drug's ability to influence the synthesis of nitrite anions and polyamines. It is shown that the LOLA drug, which is of amino acid origin and contains L-ornithine and L-aspartate, promotes the restoration of the morphofunctional state of the liver and exhibits protective properties against hepatocyte damage, preventing the development of cytolytic and cholestatic syndromes. It stimulates the synthesis of protein, urea, and polyamines, reduces endotoxicosis, improves detoxifying and metabolic processes in the liver, and restores the functioning of the pro-oxidant-antioxidant system, L-arginine-NO, and mitochondrial respiration. It is shown for the first time that LOLA implements mechanisms of cytolytic and cholestatic suppression, and endotoxicosis inhibition, as well as the activation of mitochondrial respiration in toxic hepatitis via an NO-dependent mechanism. Regarding the impact on lipid peroxidation processes and the state of the antioxidant system, it is established that LOLA achieves these effects not only through the L-arginine-NO system. A correlation between NO production levels and the synthesis of HPL, GSH content, and catalase activity has been found. Blocking the synthesis of NO did not affect the ability of LOLA to maintain a high potential of antioxidant protection in hepatitis, the activity of SOD isozymes, or the level of TBA-active products. It was established in this study that the ability of LOLA to modulate the synthesis of nitrogen oxide is not the determining factor in the hepatoprotective action of the drug in cirrhosis. This is because blocking NOS with L-NAME did not reverse the effects of LOLA on the activity of mitochondrial electron transport system enzymes, cytolysis and cholestasis indicators, lipid peroxidation indicators, namely thiobarbituric acid and GSH products. In the liver cirrhosis model, we first established a relationship in the mechanism of action of LOLA between the ability to influence nitrogen oxide synthesis and the expression of cytokines TNF-α and TGF-β, MAM concentration, GST, catalase, and SOD activity. It was shown that the ability of LOLA to influence polyamine synthesis plays a critical role in the protective effect of the drug in hepatitis and cirrhosis. Blocking polyamine synthesis with DFMO reverses most of the investigated effects of LOLA in both hepatitis and cirrhosis, and the morphological structure of the liver after administration of LOLA in combination with DFMO is characterized by deep dystrophic-necrotic changes, lymphohistiocytic and leukocytic infiltration.

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