MORPHOFUNCTIONAL STATE OF LIVER, BRAIN, AND HEART TISSUES UNDER CONDITIONS OF CHRONIC EPILEPTIC SYNDROME FORMATION AND THE USE OF RAPAMYCIN WITH PIOGLITAZONE

Abstract

Chronic epileptic syndrome represents a complex pathological condition accompanied not only by seizures but also by systemic metabolic and morphological alterations within the organism. Research into systemic changes in the liver, myocardium, and brain during the pathogenesis of this syndrome is crucial for the pathogenetic development of novel pharmacological correction methods. Particular attention is paid to comorbid conditions resembling metabolic syndrome and the search for effective ways to alleviate them through combination therapy. The aim of the study was to investigate the markers of oxidative stress, enzymatic activity of aminotransferases and alkaline phosphatase, as well as the histomorphological characteristics of liver tissue and myocardium in rats using a pentylenetetrazol (PTZ) kindling model, and to evaluate the efficacy of combined rapamycin and pioglitazone administration. We conducted the experimental study on 38 mature male Wistar rats. We modeled kindling by intraperitoneal administration of PTZ at a dose of 35.0 mg/kg for three weeks. We administered rapamycin (1.0 mg/kg) and pioglitazone (50.0 mg/kg) during the last 10 days of kindling formation. We assessed Malondialdehyde (MDA) levels, superoxide dismutase (SOD) activity, alanine and aspartate aminotransferase (ALT, AST) activity, alkaline phosphatase, and glucose levels, followed by histological analysis of tissues. Our results show that rats with developed kindling syndrome exhibit systemic oxidative stress: MDA content increased in liver tissue by 38.4% and in the brain by 41.6% (p < 0.05), while SOD activity decreased by 47.6% and 48.0%, respectively. Biochemical blood analysis showed an increase in AST activity by 42.4%, ALT by 40.8%, and alkaline phosphatase by 33.0% (p < 0.05) compared to controls. The glucose tolerance test revealed hyperglycemia (a 34.9% increase at the 90th minute). Histomorphologically, the liver showed disruption of the trabecular structure, appearance of binuclear hepatocytes, perivenular fibrosis, and mononuclear infiltration. Microhemorrhages and cardiomyocyte thickening by 32.9% (p < 0.001) were recorded in the myocardium. The combined use of rapamycin and pioglitazone effectively prevented the development of these functional and morphological disorders, demonstrating a synergistic effect. The obtained results indicate significant systemic disorders in the functioning of the liver, myocardium, and brain under conditions of PTZ-induced kindling. The combined use of rapamycin and pioglitazone exerts a pronounced hepato-, neuro-, and cardioprotective effect, justifying further investigation of this combination.