Фармакологічна корекція розладів мозку за умов експериментальної гепато-ентеральної дисфункції, спричиненої ізоніазидом і рифампіцином

Abstract

Дисертація присвячена вдосконаленню фармакокорекції енцефалопатії, спричиненої ізоніазид-рифампіцин-індукованою гепато-ентеральною дисфункцією, шляхом експериментального обґрунтування доцільності застосування S-аденозил-L-метіоніну, йогурту та лактулози, фіксованої комбінації іпідакрин/фенібут та їх сумісного використання. Встановлено, що йогурт з лактулозою максимально зменшують порушення функціонального стану та гістоструктури печінки. Найкращим чином пошкоджений кишковий мікробіом відновлює комбінація йогурт/лактулоза з S-аденозил-L-метіоніном. Іпідакрин/фенібут або S-аденозил-L-метіонін максимально покращують когнітивні функції. S-аденозил-L-метіонін, комбінації іпідакрин/фенібут чи комбінації йогурту та лактулози обмежують пошкоджувальний вплив тривалого використання протитуберкульозних препаратів на гіпокамп за рахунок активації адаптаційно-компенсаторного потенціалу нейронів, зниження структурних порушень синапсів, зменшення виразності змін ГЕБ та пошкодження астроглії.

Диссертация посвящена совершенствованию фармакокоррекции энцефалопатии, вызванной изониазид-рифампицин-индуцированной гепатоэнтеральной дисфункцией, путем экспериментального обоснования целесообразности применения S-аденозил-L-метионина, йогурта и лактулозы, фиксированной комбинации ипидакрин/фенибут и их совместного использования. Установлено, что йогурт с лактулозой максимально уменьшают нарушения функционального состояния и гистоструктуры печени. Наилучшим образом поврежденный кишечный микробиом восстанавливает комбинация йогурт/лактулоза с S-аденозил-L-метионином. Ипидакрин/фенибут или S-аденозил-L-метионин максимально улучшают когнитивные функции. S-аденозил-L-метионин, комбинация ипидакрин/фенибут или комбинация йогурта и лактулозы ограничивают повреждающее влияние длительного использования противотуберкулезных препаратов на гиппокамп за счет активации адаптационно-компенсаторного потенциала нейронов, уменьшения структурных нарушений синапсов, снижения выраженности изменений ГЭБ и повреждения астроглии.

The thesis of Kharchenko Y.V. is devoted to the study of the problem of drug correction of encephalopathy caused by isoniazid-rifampicin-induced hepato-enteral dysfunction, which consists in the experimental substantiation of the expediency of S-adenosyl-L-methionin, yogurt and lactulose, fixed combination of ipidacrine/phenibut and their combined administration as drugs with potential neuroprotective, hepatoprotective and pro- or prebiotic activity. Neuroprotective and hepatoprotective properties and pro/prebiotic activity of the drugs were evaluated in vivo and in vitro in a model of drug-induced liver injury (DILI), which was induced by repeated intragastric administration of tuberculostatics isoniazid and rifampicin at doses of 86 mg/kg respectively for 28 days. S-adenosyl-Lmethionine (S-AM) was administered at a dose of 35 mg/kg intramuscularly, a fixed combination ipidacrine/phenibut (Ip/Ph) – 1/60 mg/kg intragastrically, the composition yogurt and lactulose (Yo/Lac) –1 bil. colony forming units/kg + 2680 mg/kg intragastrically. Individual groups of animals received triple combination pharmacotherapy (S-AM + Yo/Lac, and Ip/Ph + Yo/Lac) in the above mentioned doses. Drugs and their combinations were administered for 2 weeks one hour before the use of tuberculostatics, starting from 14th day of induction of experimental pathology to identify the nature of their effect on the manifestations of cognitive dysfunction caused by isoniazid-rifampicin-induced hepato-enteral insufficiency. It was found that the course of Yo/Lac and their combined use with S-AM greatly improves energy metabolism and reduces the manifestations of hepatocytolysis, as well as carbonyl stress and structural changes in the liver caused by prolonged tuberculosis intoxication. Thus, against the background of the course of introduction of S-AM, both independently and in combination with Yo/Lac, there was a maximum decrease in pathologically increased ALT activity – by 28.8% (p<0.05) and 35.8% (p<0.05), respectively. In addition, it was determined that the use of S-AM on the background of pro/prebiotic therapy in 1.28 times (p<0.05) reduced the level of ketone phenylhydrazones (KPH) and most contributed to the approximation of the values of this marker to the level of physiological parameters. It was found that under the conditions of DILI, the use of the combination Yo/Lac, S-AM and fixed combination Ip/Ph showed comparable therapeutic efficacy, helping to reduce the lactic acid content by 79% (p<0.05), 64.2% (p<0.05) and 67.9% (p<0.05), respectively, and as close as possible to the ratio of lactate / pyruvate to the level of physiological parameters. It was noted that the co-administration of both Yo / Lac and S-AM and the combination of Ip / Ph with the pro- and prebiotic Yo / Lac did not improve the energy processes in the liver. Course administration of these drugs and their combinations helped to restore the protein content of S 100b in the liver. Administration of Ip / Ph or Yo / Lac maximally increased S100b protein levels by 80% (p <0.05). This is probably due to the fact that the hepatotropic properties of drugs may be mediated by the restoration of neural regulation of the function of this organ. At the same time, the combined administration of a Yo/Lac was characterized by the normalization of the intestinal microbiome, which was manifested by an increase in the number of Lactobacillus spp.and the number of Bifidobacterium spp. by 28.5% (p<0.05) and 13.5% (p=0.082), respectively, compared with DILI, and restored the quantitative composition of the intestinal microbiome to intact control. Combined administration of Yo/Lac is associated with an increase of 1.55 times (p<0,05), and S-АМ - with a decrease by 35% (p<0,05) of the specific activity of MMP 2 in the cytosolic fraction of the hippocampus rats. It was found that monotherapy with S-AM or a fixed combination of Ip/Ph or the use of Yo/Lac led to a marked decrease in the levels of late marker of destruction of protein molecules – KPH in hippocampus (by 1.29 (р<0.05), 1.36 (р<0.01) and 1.24 (р<0.01) times, respectively), whereas when used in combination with yogurt and lactulose, neither S-AM nor Ip/Ph had an effect on the carbonyl content derivatives in the hippocampus of rats with drug intoxication. It was found that the use of hepatoprotector S-AM, fixed combination Ip/Ph or Yo/Lac contributed to a statistically significant increase in the relative content of NCAM by 38.7% (p<0.01), 39.6% (p<0.01) and 49.2% (p<0.01), respectively. The expediency of neuroprotective therapy with S-AM, Ip/Ph and Yo/Lac under the conditions of DILI was additionally proved in the ultrastructural study of the neocortex and hippocampus. It was determined that these drugs helped to activate the adaptive-compensatory potential of neurons, reduce the disorganization of synaptic vesicles and swelling of presynaptic terminals, reduce the severity of changes in BBB and reduce damage to the hippocampal astroglia to the negative impact of processes that develop with long-term use of anti-TB drugs. Due to this, experimental drugs can prevent the processes of damage to neurons and their subsequent apoptosis, including in hepato-enteral insufficiency caused by of anti-TB drugs. This experimental study is the basis for the usage of well-known neuro- and hepatotropic drugs and their combinations in the prevention and treatment of neuronal disorders that may be associated with hepato-enteral dysfunction caused by long-term use of anti-TB drugs.