Ability of mexidol to enhance antiexudative effect of diclofenac sodium and etoricoxib in rats and mice with carrageenan-induced edema

Non-steroidal anti-inflammatory drugs (NSAIDs) are some of the most widely used drugs in existence. However, they can cause numerous side effects. Therefore, it is crucial to develop approaches to reducing the severity of their side effects. The purpose of this study is to investigate the effect of mexidol on the anti-inflammatory activity of NSAIDs, such as selective cyclooxygenase (COX)-2 inhibitor etoricoxib and non-selective COX inhibitor diclofenac sodium. Materials and methods. Effect of a single oral dose of the drugs was evaluated in rats and mice with carrageenan-induced edema by measuring the severity of edema over a period of 4 and 6 hrs, respectively. Results. Diclofenac sodium at doses of 1 and 10 mg/kg exhibits a dosedependent antiexudative effect, the effect of etoricoxib at these doses is comparable, mexidol at a dose of 25 mg/kg does not exhibit an antiexudative effect. In mice, the effect of a combination of diclofenac sodium at a dose of 1 mg/kg and mexidol at a dose of 25 mg/kg is non-inferior to diclofenac sodium at a dose of 10 mg/kg and superior the effect of diclofenac sodium at a dose of 1 mg/kg. In rats, the combination of diclofenac sodium and mexidol significantly reduces the severity of edema at 4 hrs after its induction compared with diclofenac sodium at a dose of 1 mg/ kg only. In mice, a combination of etoricoxib at a dose of 1 mg/kg and mexidol at a dose of 25 mg/kg is more effective than etoricoxib at doses of 1 and 10 mg/kg. In rats, etoricoxib at a dose of 10 mg/kg and the combination of etoricoxib at a dose of 1 mg/kg and mexidol at a dose of 25 mg/kg have a comparable effect. Conclusion. Mexidol at a low dose (25 mg/kg) enhances the antiexudative effect of diclofenac sodium and etoricoxib. And, therefore, a decrease in the dose of NSAIDs in combination with mexidol will help to reduce the side effects of these drugs.

1. Chang M.-K., Binder C.J., Miller Y.I., Subbanagounder G., Silverman G.J., Berliner J.A., Witztum J.L. Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory // J. Exp. Med. 2004. Vol. 200. N 11. P. 1359–1370.

2. Chou M.-Y., Hartvigsen K., Hansen L.F., Fogelstrand L., Shaw P.X., Boullier A., Binder C.J., Witztum J.L. Oxidationspecific epitopes are important targets of innate immunity // J. Intern. Med. 2008. Vol. 263. N 5. P. 479–488.

3. Leslie C.C. Cytosolic phospholipase A2: physiological function and role in disease // J. Lipid. Res. 2015. Vol. 56. N 8. P. 1386–1402.

4. Calder P.C. Eicosanoids // Essays Biochem. 2020. Vol. 64. N 3. P. 423–441.

5. Mitchell J.A., Akarasereenont P., Thiemermann C., Flower R.J., Vane J.R. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase // Proc. Natl. Acad. Sci. U.S.A. 1994. Vol. 90. N 24. P. 11693–11697.

6. Ricciotti E., Fitzgerald G.A. Prostaglandins and inflammation // Arterioscler. Thromb. Vasc. Biol. 2011. Vol. 31. N 5. P. 986–1000.

7. McAdam B.F., Mardini I.A., Habib A., Burke A., Lawson J.A., Kapoor S., FitzGerald G.A. Effect of regulated expression of human cyclooxygenase isoforms on eicosanoid and isoeicosanoid production in inflammation // J. Clin. Invest. 2000. Vol. 105. N 10. P. 1473–1482.

8. Smyth E.M., Grosser T., Wang M., Yu Y., FitzGerald G.A. Prostanoids in health and disease // J. Lipid Res. 2009. Vol. 50 (Suppl). P. S423–S428.

9. Crofford L.J., Wilder R.L., Ristimaki A.P., Sano H., Remmers E.F., Epps H.R., Hla T. Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues. Effects of interleukin- 1 beta, phorbol ester, and corticosteroids // J. Clin. Invest. 1994. Vol. 93. N 3. P. 1095–1101.

10. Schonbeck U., Sukhova G.K., Graber P., Coulter S., Libby P. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions // Am. J. Pathol. 1999. Vol. 155. N 4. P. 1281–1291.

11. Mardini I.A., FitzGerald G.A. Selective inhibitors of cyclooxygenase-2: a growing class of anti-inflammatory drugs // Mol. Interv. 2001. Vol. 1. N 1. P. 30–38.

12. Воронина Т.А. Мексидол: основные нейропсихотропные эффекты и механизм действия // Фарматека. 2009. Т. 180. № 6. С. 1–4.

13. Rafiee L., Hajhashemi V., Javanmard S.H. Maprotiline inhibits COX2 and iNOS gene expression in lipopolysaccharide-stimulated U937 macrophages and carrageenan-induced paw edema in rats // Cent. Eur. J. Immunol. 2019. Vol. 44. N 1. P. 15–22.

14. Kuedo Z., Sangsuriyawong A., Klaypradit W., Tipmanee V., Chonpathompikunlert P. Effects of Astaxanthin from Litopenaeus Vannamei on carrageenaninduced edema and pain behavior in mice // Molecules. 2016. Vol. 21. N 3: 382.

15. Abd-Allah A.A.M., El-Deen N.A.M.N., Mohamed W.A.M., Naguib F.M. Mast cells and proinflammatory cytokines roles in assessment of grape seeds extract anti-inflammatory activity in rat model of carrageenan-induced paw edema // Iran. J. Basic. Med. Sci. 2018. Vol. 21. N 1. P. 97–107.

16. Mitrea D.R., Malkey R., Florian T.L., Filip A., Clichici S., Bidian C., Moldovan R., Hoteiuc O.A., Toader A.M., Baldea I. Daily oral administration of chlorogenic acid prevents the experimental carrageenan-induce d oxidative stress // J. Physiol. Pharmacol. 2020. Vol. 71. N 1. P. 55–65.

17. Winter C.A., Risley E.A., Nuss G.W. Carrageenininduced edema in hind paw of the rat as an assay for antiiflammatory drugs // Proc. Soc. Exp. Biol. Med. 1962. Vol. 111. P. 544–547.

18. Иванова Е.А., Васильчук А.Г., Матюшкин А.И., Воронина Т.А. Усиление противовоспалительного и анальгетического эффекта диклофенака натрия при его применении в комбинации с мексидолом в эксперименте на грызунах // Эксперим. клин. фармакол. 2020. Т. 83. № 8. С. 38–42.

19. Хазанов В.А. Фармацевтические композиции на основе нестероидных противовоспалительных средств. Патент на изобретение RU 2191582, Бюлл. № 30. 2002.

20. Новиков В.Е., Илюхин С.А. Влияние гипоксена на эффективность кислоты ацетилсалициловой при остром воспалении // Эксперим. клин. фармакол. 2013. Т. 76. № 4. С. 32–35.

21. Smirnov L.D., Voronina T.A., Dyumaev K.M. Effect of a 3-hydroxypyridine derivative membrane modulator on pharmacological activity of some psychotropic drugs // Bull. Exp. Biol. Med. 1985. Vol. 99. N 5. P. 537–540.