DOI: https://doi.org/10.15587/2313-8416.2015.51994

Pharmacologicalmodification of thegabaergicsystem as a potentialvariant of cerebral protection in acute cerebral ischemia

Олександр Володимирович Тихоновський

Abstract


The aim is to study the possible impact of some derivatives of gamma-aminobutyric acid (GABA), piracetam, picamilon and Krebs cycle intermediates - succinate (as sodium salt) on the pathobiochemical changes in the central nervous system, that occur under experimental playing of acute ischemic tissue damage of the cerebrum.

Research methods: The study was conducted in 96 rats Wistar, who were on a standardized vivarium diet. Cerebral ischemia was caused by bond of the unilateral common carotid artery. All drugs were administered intraperitoneally once daily for 4 days after modeling of an acute cerebral ischemia after which animals were withdrawn from experiment. In the brain tissues concentrations of pyruvic, izocitric, dairy and apple acids were determined. The activity of antioxidant enzymes: catalase and superoxide dysmutaza. In addition, the brain tissues the contents of lipid peroxidation products were evaluated – diene conjugates and malonic dialdehyde. Level of brain energy production was judged by the content of the adenylic nucleotide and also phosphocreatine . The degree of destruction of the brain cells was assessed by activity of the enzyme lactate dehydrogenase in the blood and brain fraction of the creatine phosphokinase.

Research results: As a result of studies, on the 4th day of ischemia a significant carbohydrate metabolism is detected, which is reflected in the sharp strengthening of anaerobic glycolysis and reduced activity of the Krebs cycle reactions, as evidenced by a significant increase in quantity of lactate and decrease in quantity of malate, isocitrate and pyruvate.

A sharp strengthening of anaerobic glycolysis results in the accumulation of oxidized products and intermediates especially the latter product – lactic acid. Metabolic acidosis develops against the background of energy failure, which leads to activation of lipid peroxidation reactions. Courses appointment of the cyclic derivatives of GABA piracetam, especially Picamilon, resulted in significantly greater improvement in metabolic parameters compared with sodium succinate may to some extent explained by the higher bioavailability of these agents cells. The impact of these drugs on the nodal points of disturbed metabolism was almost equal and different in antioxidant activity. As to normalization of lipid peroxidation reactions Picamilon was most active.

Conclusions: Thus, as a result of the research the following conclusions may be done.

1. Bilateral bond of the common carotid artery, accompanied by severe biochemical changes in the brain tissues, that is largely similar to clinical manifestations of acute ischemic stroke.

2. Course appointment of GABA derivatives in the acute period of ischemic lesions of the tissues in varyious degrees improves metabolic status of the ischemic brain and detect different degrees of manifestation of cerebral protective action.

3. The activity of various GABA derivatives in respect to the different links of pathogenesis of ischemic stroke is not the same, that leads to insufficient sustainable improvement of impaired metabolism when used alone, in the long run may be justification for finding effective combinations of cerebral protective means with different mechanism of action.

4. Among the studied drugs, the most active and balanced action was presented by Picamilon drug


Keywords


derivatives of gamma-aminobutyric acid; acute cerebral ischemia; cerebral protection

References


Bashkyn, I. M. (1994). Farmakologichna korekcija obminnyh procesiv pry ishemii' golovnogo mozku. Eksperymental'no-klinichne doslidzhennja. Kyiv, 48.

Vereshhagin, N. V., Piradov, M. A., Suslina, Z. A. (2012). Insul't. Principy diagnostiki, lechenija i profіlaktiki. Moscow, 112.

Kadykov, A. S., Shahparonova, I. V. (2002). Hronicheskie progressirujushhie sosudistye zabolevanija golovnogo mozga i demencija. Consilium medicum, 4 (2), 71–76.

Burchinskij, S. G. (2006). Ishemija golovnogo mezga vozmozhnosti kompleksnoj farmakologicheskoj korrekcii. Ukrainskyj Vіsnyk Psihonevrologii, 14 (1), 15–18.

Anisimova, A. V., Kuzin, V. M., Kolesnikova, T. I. (2003). Kliniko-diagnosticheskie kriterii i nekotorye voprosy patogeneza rannihstadij hronicheskoj ishemii golovnogo mezga. Zhurnal Nevropatologicheskoi Psihiatrii, 8, 64–75.

Bowler, J. V. (2004). Vascular-cognitive impairment. Stroke, 35 (2), 386–388. doi: 10.1161/01.str.0000115301.12426.2b

Gusev, E. I., Skvorcova, V. I. (2007). Ishemija golovnogo mozga. Moscow: Medicina, 328.

Evans, T. L. (2012). Cognitiveenhancers: new sight on the old problem. Ann. Rev. Pharmacol. Pharmacother, 5, 34–50.

Kosarev, V. V., Babanov, S. A. (2012). Farmakoterapija discirkuljatornoj jencefalopatii: v fokuse – nootropy. Meditcinskij Sovet, 3, 54–59.

Ellergast, J. P. (2000). Gamma-aminobutyricacid mediated neurophysiological effects in the central nervous system. Brain neurophysiology. Chicago: IllinoisUniv. Press, 497–530.

Voronina, T. A., Seredenin, S. B. (1998). Nootropnye preparaty, dostizhenija i perspektivy. Jeksperemental'naya Klinicheskaya Farmakologiya, 4, 3–9.

Lysenko, G. I., Jashhenko, O. B., Himion, L. V. (2008). Hronichna cerebrovaskuljarna patologija v zagal'nolikars'kij praktyci. Simejna Med., 1, 102–105.

Mishhenko, T. S., Zdesenko, I. V., Lipskaja, A. V. (2011). Novye misheni terapevticheskogo vozdejstvija u pacientov s hronicheskoj ishemiej golovnogo mezga. Mіzhnarodnoi Nevrologichnii Zhurnal, 2, 7–17.

Nagaraja, D., Jayashree, S. (2001). Randomized study of the dopamine receptor agonistpiribedil in the treatment of mild cognitive impairment. American Journal of Psychiatry, 158 (9), 1517–1519. doi: 10.1176/appi.ajp.158.9.1517

Morozova, O. G. (2013). Nootropy v kompleksnoj terapii hronicheskoj cerebral'noj ishemii. Mіzhnarodnoi Nevrologichnii Zhurnal, 5, 143–148.

Suslina, Z. A., Maksimova, M. Ju., Fedorova, T. N. (2007). Oksidantnyj stress i osnovne napravlenija nejroprotekcii pri narushenijah mozgovogo krovoobrashhenija. Nevrologichniy Zhurnal, 4, 24–28.

Denderfield, A. P., Lewis, K., Ho, T. Y. (2009). GABA mediated vasoconstriction and vasodilatationin physiological and pathological conditions. Neurotransmitters and Neuropeptidesin Regulation of Cardiovascular System. Los Angeles: UCP Press, 189–213.

Chekman, I. S., Gubskij, Ju. I., Belenichev, I. F., Pavlov, S. V. (2010). Doklinicheskoe izuchenie specificheskoj aktivnosti potencial'nyh nejroprotektivnyh preparatov. Kyiv: DFC MOZ Ukrainy, 81.

Pavlov, S. V. (2012). Vplyv tiol'nyh antyoksadntiv na vmist stres-bilka HSP 70 u gipokampi mongol's'kyh pishhanok z gostroju ishemijeju golovnogo mozku. Farmakologija ta likars'ka toksykologija, 1 (26), 15–18.

Kolesnik, Ju. M., Belenichev, I. F., Gancheva, O. V. (2005). Signal'naja rol' aktivnyh form kisloroda v reguljacii fiziologicheskih funkcij. Patologija, 2 (1), 4–10.


GOST Style Citations


1. Башкин, І. М. Фармакологічна корекція обмінних процесів при ішемії головного мозку [Текст]: автореф. дис. … д-ра мед. наук / І. М. Башкін. – Експериментально-клінічне дослідження. – К., 1994. – 48 с.

2. Верещагин, Н. В. Инсульт. Принципы диагностики, лечения и профилактики [Текст] / Н. В. Верещагин, М. А. Пирадов, З. А. Суслина. – М., 2002. – 112 с.

3. Кадыков, А. С. Хронические прогрессирующие сосудистые заболевания головного мозга и деменция [Текст] / А. С. Кадыков, И. В. Шахпаронова // Consilium medicum. – 2002. – T. 4, № 2. – С. 71–76.

4. Бурчинский, С. Г. Ишемия головного мезга возможности комплексной фармакологической коррекции [Текст] / С. Г. Бурчинский // Український Вісник Психоневрології. – 2006. – T. 14, Bип. 1. – С. 15–18.

5. Анисимова, А. В. Клинико-диагностические критерии и некоторые вопросы патогенеза раннихстадий хронической ишемии головного мезга [Текст] / А. В. Анисимова, В. М. Кузин, Т. И. Колесникова // Журнал Невропатологічної Психиатрії. – 2003. – Вып. 8. – С. 64–75.

6. Bowler, J. V. Vascular-cognitive impairment [Text] / J. V. Bowler // Stroke. – 2004. – Vol. 35, Issue 2. – P. 386–388. doi: 10.1161/01.str.0000115301.12426.2b

7. Гусев, Е. И. Ишемия головного мoзга [Текст] / Е. И. Гусев, В. И. Скворцова. – М.: Медицина, 2007. – 328 с.

8. Evans, T. L. Cognitiveenhancers: new sight on the old problem [Text] / T. L. Evans // Ann. Rev. Pharmacol. Pharmacother. – 2012. – Vol. 5. – P. 34–50.

9. Косарев, В. В. Фармакотерапия дисциркуляторной энцефалопатии: в фокусе – ноотропы [Текст] / В. В. Косарев, С. А. Бабанов // Медицинский Совет. – 2012. – № 3. – С. 54–59.

10. Ellergast, J. P. Gamma-aminobutyricacid mediated neurophysiological effects in the central nervous system [Text] / J. P. Ellergast. – Brain neurophysiology. – Chicago: IllinoisUniv. Press, 2000. – P. 497–530.

11. Воронина, Т. А. Ноотропные препараты, достижения и перспективы [Текст] / Т. А. Воронина, С. Б. Середенин // Экспериментальная Клиническая Фармакология. – 1998. – № 4. – С. 3–9.

12. Лисенко, Г. І. Хронічна цереброваскулярна патологія в загальнолікарській практиці [Текст] / Г. І. Лисенко, О. Б. Ященко, Л. В. Хіміон // Сімейна Мед. – 2008. – № 1. – С. 102–105.

13. Мищенко, Т. С. Новые мишени терапевтического воздействия у пациентов с хронической ишемией головного мезга [Текст] / Т. С. Мищенко, И. В. Здесенко, А. В. Липская // Міжнародний Неврологічний Журнал. – 2011. – № 2. – С. 7–17.

14. Nagaraja, D. Randomized study of the dopamine receptor agonistpiribedil in the treatment of mild cognitive impairment [Text] / D. Nagaraja, S. Jayashree // American Journal of Psychiatry. – 2001. – Vol. 158, Issue 9. – P. 1517–1519. doi: 10.1176/appi.ajp.158.9.1517

15. Морозова, О. Г. Ноотропы в комплексной терапии хронической церебральной ишемии [Текст] / О. Г. Морозова // Міжнародний Неврологічний Журнал. – 2013. – № 5. – С. 143–148.

16. Суслина, З. А. Оксидантный стресс и основне направления нейропротекции при нарушениях мозгового кровообращения [Текст] / З. А. Суслина, М. Ю. Максимова, Т. Н. Федорова // Неврол. Журн. – 2007. – № 4. – С. 24–28.

17. Denderfield, A. P. GABA mediated vasoconstriction and vasodilatationin physiological and pathological conditions [Text] / A. P. Denderfield, K. Lewis, T. Y. Ho. – Neurotransmitters and Neuropeptidesin Regulation of Cardiovascular System. – Los Angeles: UCP Press, 2009. – P. 189–213.

18. Чекман, И. С. Доклиническое изучение специфической активности потенциальных нейропротективных препаратов [Текст] / И. С. Чекман, Ю. И. Губский, И. Ф. Беленичев, С. В. Павлов. – К.: ДФЦ МОЗ Украины, 2010. – 81 с.

19. Павлов, С. В. Вплив тіольних антиоксаднтів на вміст стрес-білка HSP 70 у гіпокампі монгольських піщанок з гострою ішемією головного мозку [Текст] / С. В. Павлов // Фармакологія та лікарська токсикологія. – 2012. – № 1 (26). – С. 15–18.

20. Колесник, Ю. М. Сигнальная роль активных форм кислорода в регуляции физиологических функций [Текст] / Ю. М. Колесник, И. Ф. Беленичев, О. В. Ганчева // Патология. – 2005. – Т. 2, № 1. – С. 4–10.







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