Experience Of Modeling Of Non-Alcohol Stemathegatitis With Use Of Methyonin-Holin Deficient Diet On The Mouse Of The C57BL/6 Line

M. Makarova(1), Deputy dir. of science, Ya. Gushchin(1), researcher, pathomorphologist, N. Faustova(1), PhD, senior researcher, A. Kalatanova(1), pharmacologist of group pharmacodynamics, A. Selezneva(2), PhD, Deputy Head of the Department for Research and Development, S. Glembotsky(2), Head of the department for research and development; 1-CJSC «Saint-Petersburg institute of pharmacy», 188663, Russia, Leningradskiy region, Vsevolozhskiy district, Kuzmolovskiy, st. Zavodskaya, 3. b. 245; 2-State Institute of Drugs and Good Practices, 109044, Moscow, Lavrov lane, 6 Е-mail: makarova.mn@doclinika.ru

Abstract

The research and development of new drugs for the treatment and prevention of non-alcoholic steatohepatitis (NASH) is one of the urgent problems of modern pharmacology. NASH represents a significant threat to health, so its development occurs gradually, without pronounced manifestations. The pathogenesis of NASH is considered today as the theory of «two strikes»: an increase in revenues in the liver, free fatty acids and the development of steatosis hepatocyte – «primary blow»; the reaction of oxidation of free fatty acids and the formation of products of lipid peroxidation and reactive oxygen species – oxidative stress – a «second stroke». To evaluate the effectiveness of drug candidates for the treatment and prevention of NASH, various methods are used to model this pathology in animals, each of which has its own pros and cons, as described in this article. Based on the analysis of the main existing modeling methods, the article presents the results of testing the use of a methionine-choline deficient diet in mice for the purpose of developing NASH. As a result of prolonged (28 days) application of this diet in C57bl / 6 mice, the values of key parameters characterizing the development of NASH in humans were noted. On the 29th day of the study on the background of modeling in animals, an increase of AST and concentration of inflammatory cytokines (IL6, TNF-α), oxidative stress (increasing the concentration of malondialdehyde in the liver and blood of experimental animals), fat and balloon degeneration of hepatocytes and also inflammatory liver infiltration, recorded by the results of histology. Аll marked pathological changes in experimental animals are manifestations of the main components of the pathogenesis of NASH and are observed in the clinic. This allows us to conclude that simulation NASH via inclusion in the diet of mice C57BL/6-methionine choline deficient diet is effective for the evaluation of new drugs for the treatment and prevention of NASH. Key issues in the methodology and modeling conditions of NASH are described in detail in this article.

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DOI

10.29296/2618723X-2018-02-06

Keywords

non-alcoholic steatohepatitis

oxidative stress

methionine-choline deficiency diet

pro-inflammatory cytokines

For citation

Makarova M., Gushchin Ya., Faustova N., Kalatanova A., Selezneva A., Glembotsky S. Experience Of Modeling Of Non-Alcohol Stemathegatitis With Use Of Methyonin-Holin Deficient Diet On The Mouse Of The C57BL/6 Line. Laboratory Animals for Science. 2018; 2. https://doi.org/10.29296/2618723X-2018-02-06

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