Pharmacological correction of antioxidant protection system in the brain with Vincamine within the model of multiple sclerosis

Objective. In the course of the research, the effect of vincamine (nootropic drug) on neurological status, as well as the activity of antioxidant enzymes and the level of their coding genes’ expression in the somatosensory cortex of rats within the model of experimental allergic encephalomyelitis (EAE) were being studied. Relevance: the topicality of studying the mechanisms of multiple sclerosis in the early stages of its development is dictated by the need to search for markers of the disease and its therapy before the onset of its clinical manifestation.

Materials and methods. The animals’ neurological status was studied using muscular strength, balance, tenacity and traction tests. Rates of survival and the rats’ body weight were also being evaluated. The study of activity antioxidant enzymes: superoxide dismutase (SOD), glutathione peroxidase (GPO), and glutathione reductase (GR), as well as the expression of SOD1, GPX4, GPX6, and GSR genes was conducted on the 14th and 30th day of immunization.

Results. The percentage of vincamine-injected animals’ survival was 100% versus 87% among rats that were not injected with the nootropic drug during immunization (р<0,05) . Besides, after the injection of vincamine, a less significant decrease in body weight (р<0,01) and a less pronounced neurological deficit (р<0,05) in comparison with immunized non-injected animals were reported. The vincamine injection contributed to an increase in all studied antioxidant enzymes’ activity and the level of their genes’ expression in the somatosensory cortex.

Conclusion. Against the background of vincamine injection, a minimization of neurological deficit is being observed, probably due to a decrease in oxidative stress in the rat brain during the clinical stage of experimental allergic encephalomyellitis.

1. Арутюнян А.В., Дубинина Е.Е., Зыбина Н.Н. Методы оценки свободнорадикального окисления и антиоксидантной системы организма: методические рекомендации. Методические рекомендации. Санкт-Петербург, 2008. 104 с.

2. Карантыш Г.В., Гафиятуллина Г.Ш., Менджерицкий А.М., Прокофьев В.Н., Жукова М.В., Макаров В.А. Влияние виндебурнола на неврологический статус и морфологические изменения в головном мозге крыс в модели экспериментального аллергического энцефаломиелита. Современные проблемы науки и образования. 2018;(1):84

3. Луцкий М.А., Земсков А.М., Разинкин К.А. Биохимические маркеры окислительного стресса при различных клинических формах и стадиях течения рассеянного склероза. Журнал неврологии и психиатрии им. С.С. Корсакова. 2014;114(11):74-77

4. Пажигова З.Б., Карпов С.М., Шевченко П.П., Бурнусус Н.И. Распространенность рассеянного склероза в мире (обзорная статья). Международный журнал экспериментального образования. 2014;1(2):78-82

5. Саркисян О.Г. Новые возможности прогнозирования атрофических изменений во влагалищной ткани у женщин в пострепродуктивном периоде. Кубанский научный медицинский вестник. 2016;6(161):118-122

6. Стратегия развития медицинской науки в Российской Федерации на период до 2025 года, 2012

7. Abdel-Salam O.M.E., Hamdy S.M., Seadawy S.A.M. et al. Effect of piracetam, vincamine, vinpocetine, and donepezil on oxidative stress and neurodegeneration induced by aluminum chloride in rats. Comp Clin Path. 2016;(25):305-318. DOI: 10.1007/s00580-015-2182-0

8. Abramets I.I., Kuznetsov Y.V., Evdokimov D.V., Zaika T.O. Piracetam potentiates neuronal and behavioral effects of ketamine. Research Results in Pharmacology. 2019;5(2):49-55. DOI: 10.3897/rrpharmacology.5.35530

9. Adamczyk B., Adamczyk-Sowa M. New Insights into the Role of Oxidative Stress Mechanisms in the Pathophysiology and Treatment of Multiple Sclerosis. Oxid Med Cell Longev. 2016;(2016):1973834. DOI: 10.1155/2016/1973834

10. Aharoni R., Schottlender N., Bar-Lev D.D., Eilam R., Sela M., Tsoory M., Arnon R. Cognitive impairment in an animal model of multiple sclerosis and its amelioration by glatiramer acetate. Sci Rep. 2019;9(1):4140. DOI: 10.1038/s41598-019-40713-4

11. Beutler E. Red cell metabolism: A Manual of Biochemical Methods. Grune and Stratton, 1975. 160 p.

12. Cerqueira J.J., Compston D.A.S., Geraldes R., Rosa M.M., Schmierer K., Thompson A., Tinelli M., Palace J. Time matters in multiple sclerosis: can early treatment and long-term follow-up ensure everyone benefits from the latest advances in multiple sclerosis? J Neurol Neurosurg Psychiatry. 2018;89(8):844-850. DOI: 10.1136/jnnp-2017-317509

13. Combs D.J., D'Alecy L.G. Motor performance in rats exposed to severe forebrain ischemia: effect of fasting and 1,3-butanediol. Stroke. 1987;18(2):503-511. DOI: 10.1161/01.str.18.2.503

14. Degano A.L., Roth G.A. Passive transfer of experimental autoimmune encephalomyelitis in Wistar rats: dissociation of clinical symptoms and biochemical alterations. J Neurosci Res. 2000;59(2):283-290. DOI: 10.1002/(sici)1097-4547(20000115)59:2<283::aid-jnr15>3.0.co;2-s

15. Fetisova E., Chernyak B., Korshunova G., Mun-tyan M., Skulachev V. Mitochondria-targeted Antioxidants as a Prospective Therapeutic Strategy for Multiple Sclerosis. Curr Med Chem. 2017;24(19):2086-2114. DOI: 10.2174/0929867324666170316114452

16. Forslin M., Fink K., Hammar U., von Koch L., Johansson S. Predictors for Employment Status in People with Multiple Sclerosis: A 10-Year Longitudinal Observational Study. Arch Phys Med Rehabil. 2018;99(8):1483-1490. DOI: 10.1016/j.apmr.2017.12.028

17. Fisniku L.K., Chard D.T., Jackson J.S., Anderson V.M., Altmann D.R., Miszkiel K.A., Thompson A.J., Miller D.H. Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol. 2008;64(3):247-254. DOI: 10.1002/ana.21423

18. Günzler W.A., Flohé L. Glutathione peroxidase. In: Greenwald R.A., editor. Handbook of methods for oxygen research. Boca Raton, Florida: CRC Press, 1985. 285-290

19. Kuhlmann T., Ludwin S., Prat A., Antel J., Brück W., Lassmann H. An updated histological classification system for multiple sclerosis lesions. Acta Neuropathol. 2017;133(1):13-24. DOI: 10.1007/s00401-016-1653-y

20. Livak K.J., Schmittgen T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402-408. DOI: 10.1006/meth.2001.1262

21. Lubetzki C., Zalc B., Williams A., Stadelmann C., Stankoff B. Remyelination in multiple sclerosis: from basic science to clinical translation. Lancet Neurol. 2020;19(8):678-688. DOI: 10.1016/S1474-4422(20)30140-X

22. Lunde H.M.B., Assmus J., Myhr K.M., Bø L., Grytten N. Survival and cause of death in multiple sclerosis: a 60-year longitudinal population study. J Neurol Neurosurg Psychiatry. 2017;88(8):621-625. DOI: 10.1136/jnnp-2016-315238

23. Malpas C.B., Manouchehrinia A., Sharmin S., Roos I., Horakova D., Havrdova E.K., Trojano M., Izquierdo G. et al. Early clinical markers of aggressive multiple sclerosis. Brain. 2020;143(5):1400-1413. DOI: 10.1093/brain/awaa081

24. Mannie M., Swanborg R.H., Stepaniak J.A. Experimental autoimmune encephalomyelitis in the rat. Curr Protoc Immunol. 2009;Chapter 15:Unit 15.2. DOI: 10.1002/0471142735.im1502s85

25. Michaličková D., Hrnčíř T., Canová N.K., Slanař O. Targeting Keap1/Nrf2/ARE signaling pathway in multiple sclerosis. Eur J Pharmacol. 2020;(873):172973. DOI: 10.1016/j.ejphar.2020.172973

26. Miller E.D., Dziedzic A., Saluk-Bijak J., Bijak M. A Review of Various Antioxidant Compounds and their Potential Utility as Complementary Therapy in Multiple Sclerosis. Nutrients. 2019;11(7):1528. DOI: 10.3390/nu11071528

27. Okuda D.T., Mowry E.M., Beheshtian A., Waubant E., Baranzini S.E., Goodin D.S., Hauser S.L., Pelletier D. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology. 2009;72(9):800-805. DOI: 10.1212/01.wnl.0000335764.14513.1a

28. Paxinos G.T., Watson Ch. The Rat Brain in Stereotaxic Coordinates. (Fourth Edition). Academic Press. San Diego, California, USA: Academic Press. 1998. 256p.

29. Pegoretti V., Swanson K.A., Bethea J.R., Probert L., Eisel U.L.M., Fischer R. Inflammation and Oxidative Stress in Multiple Sclerosis: Consequences for Therapy Development. Oxid Med Cell Longev. 2020;(2020):7191080. DOI: 10.1155/2020/7191080

30. Polak P.E., Kalinin S., Braun D., Sharp A., Lin S.X., Feinstein D.L. The vincamine derivative vindeburnol provides benefit in a mouse model of multiple sclerosis: effects on the Locus coeruleus. J Neurochem. 2012;121(2):206-216. DOI: 10.1111/j.1471-4159.2012.07673.x

31. Popova N.F., Kamchatnov P.R., Riabukhina O.V. Omaron in the complex treatment of patients with multiple sclerosis. S.S. Korsakov J of Neurology and Psychiatry. 2010;110(11):17-20.

32. Raine C.S. Multiple sclerosis: The resolving lesion revealed. J Neuroimmunol. 2017;(304):2-6. DOI: 10.1016/j.jneuroim.2016.05.021

33. Ruano L., Portaccio E., Goretti B., Niccolai C., Severo M., Patti F., Cilia S., Gallo P. et al. Age and disability drive cognitive impairment in multiple sclerosis across disease subtypes. Mult Scler. 2017;23(9):1258-1267. DOI: 10.1177/1352458516674367

34. Sivalingam K., Samikkannu T. Neuroprotective Effect of Piracetam against Cocaine-Induced Neuro Epigenetic Modification of DNA Methylation in Astrocytes. Brain Sci. 2020;10(9):611. DOI: 10.3390/brainsci10090611

35. Solaro C., Ponzio M., Moran E., Tanganelli P., Pizio R., Ribizzi G., Venturi S., Mancardi G.L. et al. The changing face of multiple sclerosis: Prevalence and incidence in an aging population. Mult Scler. 2015;21(10):1244-1250. DOI: 10.1177/1352458514561904

36. Tárnok K., Kiss E., Luiten P.G., Nyakas C., Tihanyi K., Schlett K., Eisel U.L. Effects of Vinpocetine on mitochondrial function and neuroprotection in primary cortical neurons. Neurochem Int. 2008;53(6-8):289-295. DOI: 10.1016/j.neuint.2008.08.003

37. Thompson A.J., Banwell B.L., Barkhof F., Carroll W.M., Coetzee T., Comi G., Correale J., Fazekas F. et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173. DOI: 10.1016/S1474-4422(17)30470-2