MONOPHENOL TS-13 IMPROVES SURVIVAL IN MICE INFECTED WITH VIRULENT Mycobacterium tuberculosis

Author: Kozhin P.M.¹, Kovner A.V.², Zenkov N.K.³, Petrenko T.I.⁴, Kandalintseva N.V.⁵, Menshchikova E.B.⁶

Abstract

The aim of the study was to determine the dose of a virulent strain of Mycobacterium tuberculosis H37Rv that is optimal for modeling experimental tuberculosis granulomatosis in mice and to investigate the effect of the original inductor of the Keap1/Nrf2/ARE system TS-13 (sodium 3- (3'-tert-butyl-4'-hydroxyphenyl) propylthiosulfonate) on animal survival and the dynamics of granuloma formation. Material and methods. Generalized tuberculosis granulomatosis was modeled by a single injection into the tail vein of male BALB/c mice of the 2-month-old M. tuberculosis strain H37Rv at doses of 10⁶, 10⁷ and 10⁸ microbial bodies. Another group of animals on the day of infection with M. tuberculosis (10⁷ microbial bodies) began to receive TS-13 with drinking water (100 mg/kg body weight). Survival was fixed daily; after 5 weeks, mice were euthanized and liver samples were taken for histological examination. Results and discussion. The dose of 10⁷ microbial bodies was found to be the most adequate when modeling in BALB/c mice the tuberculosis granulomatosis caused by the intravenous injection of virulent M. tuberculosis strain H37Rv. At the 36^th day after the injection of 10⁷ microbial bodies, mortality was significantly lower in the group of mice receiving the inducer of the signal system Keap1/Nrf2/ARE monophenol TS-13 with drinking water (44 and 15% mice survived, respectively). At the same time, these two groups did not differ in the number and diameter of liver granulomas. The results show a high prospect of studying the role of oxidative stress and the redox-sensitive signal system Keap1/Nrf2/ARE in tuberculosis granulomatosis.

Key words

H37Rv, synthetic monophenol TS-13, Keap1/Nrf2/ARE system, tuberculosis

References

Harvey C.J., Thimmulappa R.K., Sethi S., Kong X., Yarmus L., Brown R.H., Feller-Kopman D., Wise R., Biswal S. Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model // Sci. Transl. Med. 2011. 3. (78). 78ra32.

Kozhin P.M., Zenkov N.K., Chechushkov A.V., Zaitseva N.S., Kandalintseva N.V., Menshchikova E.B. Redox-sensitive system of antioxidant response element as a new target for tuberculosis treatment. Acta Biomed. Sci. 2016. 1. (3-2). 92-95. [In Russian].

Kozhin P.M., Zenkov N.K., Lemza A.E., Chechushkov A.V., Zaitseva N.S., Kandalintseva N.V., Menshchikova E.B. Induction of redox-sensitive Keap1/Nrf2/ARE system alters classical activation of macrophages. Sibirskiy nauchnyy medtsinskiy zhurnal = Siberian Scientific Medical Journal. 2015. 35. (6). 37-44. [In Russian].

Menshchikova E., Tkachev V., Lemza A., Sharkova T., Kandalintseva N., Vavilin V., Safronova O., Zenkov N. Water-soluble phenol TS-13 combats acute but not chronic inflammation // Inflamm. Res. 2014. 63. (9). 729-740.

Menshchikova E., Zenkov N., Tkachev V., Potapova O., Cherdantseva L., Shkurupiy V. Oxidative stress and free-radical oxidation in BCG granulomatosis development // Oxid. Med. Cell. Longev. 2013. 2013. 452546.

Menshchikova E.B., Zenkov N.K., Chechushkov A.V., Kozhin P.M., Cherdantseva L.A., Sharkova T.V., Potapova O.V., Lyubimov G.Yu., Lyubimova G.A., Yagunov S.Ye. The involvement of reactive oxygen species and redox-sensitive signaling system Keap1/Nrf2/ARE in the development of granulomatous inflammation. Sibirskiy nauchnyy medtsinskiy zhurnal = Siberian Scientific Medical Journal. 2015. 35. (2). 31-36. [In Russian].

Nairz M., Schleicher U., Schroll A., Sonnweber T., Theurl I., Ludwiczek S., Talasz H., Brandacher G., Moser P.L., Muckenthaler M.U., Fang F.C., Bogdan C., Weiss G. Nitric oxide-mediated regulation of ferroportin-1 controls macrophage iron homeostasis and immune function in Salmonella infection // J. Exp. Med. 2013. 210. (5). 855-873.

Oberley-Deegan R.E., Lee Y.M., Morey G.E., Cook D.M., Chan E.D., Crapo J.D. The antioxidant mimetic, MnTE-2-PyP, reduces intracellular growth of Mycobacterium abscessus // Am. J. Respir. Cell Mol. Biol. 2009. 41. (2). 170-178.

Oberley-Deegan R.E., Rebits B.W., Weaver M.R., Tollefson A.K., Bai X., McGibney M., Ovrutsky A.R., Chan E.D., Crapo J.D. An oxidative environment promotes growth of Mycobacterium abscessus // Free Radic. Biol. Med. 2010. 49. (11). 1666-1673.

Palanisamy G.S., Kirk N.M., Ackart D.F., Shanley C.A., Orme I.M., Basaraba R.J. Evidence for oxidative stress and defective antioxidant response in Guinea pigs with tuberculosis // PLoS One. 2011. 6. (10). e26254.

Shintyapina A.B., Vavilin V.A., Safronova O.G., Lyakhovich V.V. The gene expression profile of a drug metabolism system and signal transduction pathways in the liver of mice treated with tert-butylhydroquinone or 3-(3'-tert-butyl-4'-hydroxyphenyl)propylthiosulfonate of sodium // PLoS One. 2017. 12. (5). e0176939.

Shkurupiy V.A., Menshchikova E.B., Tkachev V.O., Zenkov N.K. Changes in activity of free radical oxidation processes in the early stages of BCG granulomatosis // Bull. Exp. Biol. Med. 2012. 154. (2). 213-216.

Thimmulappa R.K., Lee H., Rangasamy T., Reddy S.P., Yamamoto M., Kensler T.W., Biswal S. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis // J. Clin. Invest. 2006. 116. (4). 984-995.

Tkachev V., Menshchikova E., Zenkov N., Zaitseva N., Lemza A., Sharkova T., Kandalintseva N., Yagunov S. Antioxidant response element activating sulfur-containing monophenols as novel anti-inflammatory agents // Free Radic. Biol. Med. 2010. 49. S149.

Vasilyeva I.A, Belilovsky E.M., Borisov S.E., Sterlikov S.A. Morbidity, mortality and prevalence as indicators of tuberculosis burden in the WHO regions, the countries of the world and in the Russian Federation. Part 1. Incidence and prevalence of tuberculosis. Tuberkulez i bolezni legkikh = Tuberculosis and Lung Diseases. 2017. 95. (6). 9–21. [In Russian].

World Health Organization. Global tuberculosis report 2017. WHO, 2017. http://apps.who.int/iris/bitstream/10665/259366/259361/9789241565516-eng.pdf?ua=9789241565511

Zenkov N.K., Kozhin P.M., Chechushkov A.V., Martinovich G.G., Kandalintseva N.V., Menshchikova E.B. Mazes of Nrf2 Regulation. Biochemistry (Mosc.). 2017. 82. (5). 556-564.

Zenkov N.K., Menshchikova E.B., Kandalintseva N.V., Oleynik A.S., Prosenko A.E., Gusachenko O.N., Shklyaeva O.A., Vavilin V.A., Lyakhovich V.V. Antioxidant and antiinflammatory activity of new water-soluble sulfur-containing phenolic compounds. Biochemistry (Mosc). 2007. 72. (6). 644–651.

About Authors (Correspondence):

Menshchikova E.B. – doctor of medical sciences, head of the laboratory of molecular mechanisms of free radical processes, e-mail: lemen@centercem.ru

Full Text

snmzh_1-2018_kozhin_i_dr.pdf

Received: 26/02/2018

Accepted: 26/02/2018