CARNOSINE PREVENTS THE DEVELOPMENT OF OXIDATIVE STRESS IN THE CONDITIONS OF TOXIC ACTION OF CADMIUM

Protective effect of the natural dipeptide carnosine on the antioxidant system of rats in conditions of oxidative stress caused by the chronic cadmium administration was investigated. Oxidative status of experimental animals were evaluated on a number of informative parameters of iron-induced chemiluminescence. It is shown that the introduction of cadmium for 7 days reduces the duration of the latent period of chemiluminescence in the brain, liver and blood plasma suggesting the depletion of endogenous antioxidant defense. Co-exposure to carnosine and cadmium led to significant increase in the level of antioxidant protection in plasma, liver and brain of animals. Carnosine also prevented the increase of lipid hydroperoxides in the brain and prevented the development of lipid peroxidation content in liver and plasma of animals. Mechanism of the protective effect of carnosine in conditions of oxidative stress inducing by cadmium administration shown on human neuroblastoma SH-SY5Y cell culture. Adding to the incubation medium to a final concentration of cadmium 5 μM reduced cell viability of a culture that was determined by MTT assay; simultaneously introducing carnosine (0.25 mM final concentration) with cadmium resulted in increased cell viability at 24 hours of incubation. Thus carnosine in a final concentration of 1 mM effectively prevented the development of necrotic lesions neuroblastoma cells, inhibiting the formation of reactive oxygen species as measured by flow cytometry. The results indicate the ability of carnosine to prevent the development of oxidative stress under the toxic action of cadmium. 

1. Brzoska M.M., Majewska K., Kupraszewicz E. Effects of low, moderate and relatively high chronic exposure to cadmium on long bones susceptibility to fractures in male rats // Environ. Toxicol. Pharmacol. 2010. Vol. 29. N 3. P. 235–245.

2. Hammond P.B., Foulkes E.C. Metal ion toxicity in man and animals // Metal ions in biological systems / Ed. H. Sigel. N.Y.: Marcel Dekker, 1986. P. 157–200.

3. Satoh M., Koyama H., Kaji T., Kito H., Tohyama C. Perspectives on cadmium toxicity research // Tohoku J. Exp. Med. 2002. Vol. 196. N 1. P. 23–32.

4. Thompson J., Bannigan J. Cadmium: toxic effects on the reproductive system and the embryo // Reprod. Toxicol. 2008. Vol. 25. N 3. P. 304–315.

5. Jiang L.F., Yao T.M., Zhu Z.L., Wang C., Ji L.N. Impacts of Cd(II) on the conformation and self-aggregation of Alzheimer’s tau fragment corresponding to the third repeat of microtubule-binding domain // Biochim. Biophys. Acta. 2007. N 1774. P. 1414–1421.

6. Lukawski K., Nieradko B., Sieklucka-Dziuba M. Effects of cadmium on memory processes in mice exposed to transient cerebral oligemia // Neurotoxicol. Teratol. 2005. N 27. P. 575–584.

7. Иноземцев А.Н., Бокиева С.Б., Карпухина О.В., Гумаркалиева К.З. Влияние сочетанного воздействия тяжелых металлов и пирацетама на обучение и память крыс // Докл. РАН. 2008. Т. 422. № 5. С. 700–703.

8. Фролова Н.А. Биологическое действие кадмия при хроническом воздействии в антенатальный и постнатальный периоды развития крыс // Токсикол. Вестник. 2007. № 1. С. 11–14.

9. Watjen W., Beyersmann D. Cadmium-induced apoptosis in C6 glioma cells: influence of oxidative stress // Biometals. 2004. Vol. 17. N 1. P. 65–78.

10. Abu-Taweel G.M., Ajarem J.S., Ahmad M. Protective Effect of curcumin on anxiety, learning behavior, neuromuscular activities, brain neurotransmitters and oxidative stress enzymes in cadmium intoxicated mice // J. Behav. Brain Science. 2013. N 3. P. 74–84.

11. Jomova K., Valko M. Advances in metal-induced oxidative stress and human disease // Toxicology. 2011. Vol. 283. N 2-3. P. 65–87.

12. Nishimura Y., Yamaguchi J.Y., Kanada A., Horimoto K., Kanemaru K., Satoh M., Oyama Y. Increase in intracellular Cd2+ concentration of rat cerebellar granule neurons incubated with cadmium chloride: cadmium cytotoxicity under external Ca2+ -free condition // Toxicol. In Vitro. 2006. Vol. 20. N 2. P. 211–216.

13. Jimi S., Uchiyama M., Takaki A., Suzumiya J., Hara S. Mechanisms of сell death Induced by cadmium and arsenic // Ann. N.Y. Acad. of Sci. 2004. Vol. 1011. N 1. P. 325–331.

14. Halliwell B., Gutteridge J.M.C. Free radical in biology and medicine, 3rd ed. N.Y.: Oxford Univ. Press, 1999. 617– 783 p.

15. Федорова Т.Н., Максимова М.Ю., Варакин Ю.Я., Логвиненко А.А., Гнедовская Е.В., Суслина З.А. Окисляемость липопротеинов крови у пациентов с нарушениями мозгового кровообращения // Анналы клин. и эксперим. неврологии. 2014. Т. 8. № 1. С. 30–33.

16. Болдырев А.А. Карнозин и защита тканей от окислительного стресса. М.: Диалог-МГУ, 1999. 364 с.

17. Berezhnoy D.S., Bokieva S.B., Stvolinskii S.L., Fedorova T.N., Inozemtsev A.N. Effect of carnosine on conditioned passive avoidance response in the norm and under hypoxia conditions // Moscow Univ. Biol. Sci. Bull. 2015. Vol. 70. N 3. P. 105–109.

18. Boldyrev A.A. Carnosine: new concept for the function of an old molecule // Biochemistry (Mosc). 2012. Vol. 77. N 4. P. 313–326.

19. Абаимов Д.А., Сариев А.К., Танкевич М.В., Пантюхова Е.Ю. Прохоров Д.И., Федорова Т.Н., Лопачев А.В., Стволинский С.Л., Коновалова Е.В., Сейфулла Р.Д. Исследование базовых фармакокинетических характеристик и эффективности проникновения в ткань мозга дипептида карнозина в эксперименте // Эксп. клин. фармакол. 2015. Т. 78. № 3. С. 30–35.

20. Федорова Т.Н., Реброва О.Ю., Ларский Э.Г. Микромодефикация метода определения активности процессов свободнорадикального окисления // Лабораторное дело. 1991. № 3. С. 37–39.

21. Akkuratov E.E., Lopacheva O.M., Kruusmägi M., Lopachev A.V., Shah Z.A., Boldyrev A.A., Liu L. Functional interaction between Na/K-ATPase and NMDA receptor in cerebellar neurons // Cell. Mol. Neurobiol. 2015. Vol. 52. N 3. P. 1726–1734.

22. Boldyrev A., Song R., Djatlov V., Lawrence D., Carpenter D. Neuronal cell death and reactive oxigen species // Cell Mol. Neurobiol. 2000. Vol. 20. N 4. P. 433–450.

23. Федорова Т.Н., Куликова О.И., Стволинский С.Л., Орлова В.С. Протекторное действие (S)-тролокс-карнозина на культуру клеток нейробластомы человека SH-SY5Y в условиях токсичности тяжелых металлов // Нейрохимия. 2016. Т. 33. № 1. С. 63–69.

24. Федорова Т.Н., Стволинский С.Л., Куликова О.И., Коновалова Е.В., Левачева И.С., Самсонова О., Баковский У. Эффективность нейропротекторного действия новых производных природного антиоксиданта карнозина в условиях окислительного стресса in vitro и in vivo // Анналы клин. и эксперим. неврологии. 2016. Т. 10. № 1. С. 47–52.

25. Stvolinsky S.L., Bulygina E.R., Fedorova T.N., Meguro K., Sato T., Tyulina O.V., Abe H., Boldyrev A.A. Biological activity of novel synthetic derivatives of carnosine // Cell. Mol. Neurobiol. 2010. Vol. 30. N 3. 395–404.