METABOLIC CORRECTION OF CEREBRAL DISORDERS IN ACUTE OBSTRUCTIVE CHOLESTASIS (EXPERIMENTAL STUDY)

Aim. To research cerebral functional and structural disorders in acute obstructive cholestasis and possibilities of their metabolic correction.

Material and Methods. Acute obstructive cholestasis was simulated by common bile duct compression in 26 anesthetized dogs which were divided into three series.

The first group included cholestasis dogs without treatment. In the second group common bile duct (CBD) was decompressed in 3 days postoperatively and 0.9% sodium chloride solution (20 ml / kg) was administered for 5 days. In the 3^rd group Mexidol® (6.5 mg / kg) and Cortexin® (10 mg / kg) were injected additionally after CBD decompression. In blood plasma and cerebral homogenate malondialdehyde (MDA) and catalase levels were determined. Brain tissue histological investigation was performed with 200x and 400x magnification.

Results. In the 1^st series on the 10^th day MDA and catalase levels in cerebral homogenate were 4.1 times higher and 4.3     times lower than those in control animals. Structural changes were presented by perivascular and pericellular edema, reduction of capillary volume, vacuolization and atrophy of neurons. In the 2^nd series there were 2.15-fold and 1.2-fold decrease of MDA in systemic circulation and in cerebral tissue respectively. Catalase activity was increased up to 1.36 and 1.22 times (p > 0.05) accordingly. Cerebral structural disorders were the same. In the 3rd series there were 2.91-fold and 3.77-fold decrease of MDA in systemic circulation and in cerebral homogenate respectively in 10 days postoperatively. Catalase activity was increased up to 1.57 and 4.76 times (p < 0.001) accordingly. Structural normalization was accompanied by increase of microcirculatory volume, elimination of vacuolization and atrophy of neurons, reduction of cerebral edema.

Conclusion. Mexidol® and Cortexin® reduce significantly the processes of free-radical oxidation in the brain and contributes to normalization of structural disorders.

1. Smolirn S.P., Petrova M.M., Sharobaro V.I., Fedorov G.N., Yakubov D.A. The clinical course of hepatic encephalopathy in patients with sub- and decompensated alcoholic liver cirrhosis during treatment with antioxidant. Vestnik novykh meditsinskikh tekhnologiy. Elektronnoye izdaniye. 2013; 1. http://medtsu.tula.ru/VNMT/NewMedTechn.html (In Russian)

2. Vaquero J., Chung C., Blei A.T. Brain edema in acute liver failure. A window to the pathogenesis of hepatic encephalopathy. Ann. Hepatol. 2003; 2 (1): 12—22. PMID: 15094701.

3. Bemeur С., Desjardins P., Butterworth R.F. Evidence for oxidative/nitrosative stress in the pathogenesis of hepatic encephalopathy. Metab. Brain Dis. 2010; 25 (1): 3—9. doi: 10.1007/s11011-010-9177-y. PMID: 20195724.

4. Desjardins P., Du T, Jiang W., Peng L., Butterworth R.F Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure: role of glutamine redefined. Neurochem. Int. 2012; 60 (7): 690—696. doi: 10.1016/j.neuint.2012.02.001. PMID: 22382077.

5. Butterworth R.F. The liver-brain axis in liver failure: neuroinflammation and encephalopathy. Nat. Rev. Gastroenterol. Hepatol. 2013; 10 (9): 522—528. doi: 10.1038/nrgastro.2013.99. PMID: 23817325.

6. Rovira A., Alonso J., Cordoba J. MR imaging findings in hepatic encephalopathy. AJNR Am. J. Neuroradiol. 2008; 29 (9): 1612—1621. doi: 10.3174/ajnr.A1139. PMID: 18583413.

7. Cash W.J., McConville P., McDermott E., McCormick P.A., Callender M.E., McDougall N.I. Current concepts in the assessment and treatment of hepatic encephalopathy. QJM. 2010; 103 (1): 9—16. doi: 10.1093/qjmed/hcp152. PMID: 19903725.

8. Polunim T.E., Mayev I.V. Hepatic encephalopathy: treatment strategy selection. Meditsinskiy sovet. 2011; 5—6: 101—105. (In Russian)

9. Zaitsevа O.E. The pathophysiological aspects of hepatic encephalopathy. Vestnik neotlozhnoy i vosstanovitelnoy meditsiny. 2013; 14 (3): 403—411. (In Russian)

10. Nadinskaya M.Yu., Podymova S.D. Liver diseases and hepatic encephalopathy. Recept. 2006; 4 (48): 132—136. (In Russian)

11. Jover-Cobos M., Khetan V., Jalan R. Treatment of hyper­ammonemia in liver failure. Curr. Opin. Clin. Nutr. Metab. Care. 2014; 17 (1): 105—110. doi: 10.1097/MCO.0000000000000012. PMID: 24281376.

12. Zor'kina A.V., Makedonskaya O.G., Byakin S.P., Fedoseikin I. V., Makhrov V.I. Effects of2-ethyl-6-methyl-3-hydroxypyridine succinate on lipid peroxidation and antioxidant defense in erythrocytes during storage of donor erythrocyte mass. Human Physiology. 2009; 35 (5): 647—649.

13. D'yakonov M.M., Shabanov P.D. By the question of neuroprotective effect of peptide drugs. Vestnik Rossiyskoy voyenno-meditsinskoy akademii. 2011; 1: 255—258. (In Russian)

14. Rukovodstva dlja raboty komitetov po jetike, provodjashhih jekspertizu biomedicinskih issledovanij [Guidelines for Ethics Committees conducting examination of biomedical researches]; translated from English under the scientific editorship of O.I. Kubar, E.J. Barmans, E.A. Volsky. Moscow — St. Petersburg: NEC PMA, 2000. 32 р. (In Russian)

15. Korolyuk M.A., Ivan^ I.G., Mayorova V.I., Tokarev V.E. Method for determination of catalase activity. Laboratornoye delo. 1988; 1: 16—17. (In Russian)

16. Chroni E., Patsoukis N., Karageorgos N., Konstantinou D., Georgiou C. Brain oxidative stress induced by obstructive jaundice in rats. J. Neuropathol. Exp. Neurol. 2006; 65 (2): 193—198. PMID: 16462210.

17. Bulavintsev A.G., Podshivalova A.K., Butorina N.V. The sensitivity of animals brain to pro-oxidant factors. Vestnik Irkutskoy gosudarstvennoy sel'skokhozyaystvennoy akademii. 2013; 56: 68—75. (In Russian)

18. Yu L., Jiang R., Su Q., Yu H., Yang J. Hippocampal neuronal metal ion imbalance related oxidative stress in a rat model of chronic aluminum exposure and neuroprotection of meloxicam. Behav. Brain Funct. 2014; 10: 6. doi: 10.1186/1744-9081-10-6. PMID: 24618126.