Dejstvo finasterida na bihejvioralne, elektroencefalografske i ćelijske promene u hepatičnoj encefalopatiji izazvanoj tioacetamidom kod pacova

Abstract

Hepatiĉna encefalopatija (HE) predstavlja neuropsihijatrijski sindrom, koji se razvija kao posledica akutne ili hroniĉne insuficijencije jetre. Za ispitivanje patogeneze HE koriste se razliĉiti eksperimentalni modeli, ukljuĉujući model izazvan portno-kavnim šantom, stenozom portne vene, modele izazvane hepatotoksiĉnim agensima (tioacetamid, D-galaktozamin, paracetamol, azoksimetan, ugljen-tetrahlorid) i modele ciroze jetre. U razvoju HE kljuĉnu ulogu ima hiperamonijemija, a mehanizmi ukljuĉeni u patogenezu HE ukljuĉuju: citotoksiĉni edem mozga, poremećaje neurotransmisije (preteţno glutamatergiĉke i GABA-ergiĉke), energetske poremećaje, oksidacijski stres, mitohondrijsku disfunkciju i neuroinflamaciju. U HE povećava se sinteza neurosteroida, koji pozitivnom alosternom modulacijom receptora za gama-aminobuternu kiselinu (GABAA receptora) pojaĉavaju efekte GABA u centralnom nervnom sistemu. Finasterid, inhibitor 5α-reduktaze i sinteze neurosteroida, potencijalno moţe menjati tok HE. Ciljevi ove disertacije su bili: da se ispitaju bihejvioralne i elektroencefalografske (EEG) promene u HE izazvanoj tioacetamidom kod pacova; da se odrede parametri oksidacijskog stresa i antioksidacijske zaštite, aktivnost acetilholinesteraze (AchE) i ekspresiju ćelijskih markera u razliĉitim moţdanim regionima u intoksikaciji tioacetamidom; da se ispita uticaj finasterida na bihejvioralne, EEG i ćelijske promene u HE izazvanoj tioacetamidom kod pacova. U cilju ispitivanja efekata tioacetamida (TAA) na ponašanje, EEG i ćelijske promene muţjaci Wistar pacova su podeljeni u sledeće grupe: 1. kontrolna grupa (n=8); 2. eksperimentalna grupa tretirana TAA na dozno zavisan naĉin: TAA300 (300 mg/kg, n=8), TAA600 (600 mg/kg, n=10) i TAA900 (900 mg/kg, n=18). Dnevne doze TAA (300 mg/kg) su primenjene tokom jednog (TAA300), dva (TAA600) ili tri uzastopna dana (TAA900). U cilju ispitivanja uticaja finasterida na HE izazvanu TAA-om, ţivotinje su podeljene u sledeće grupe: 1. kontrolna grupa (n=8); 2. TAA900 grupa tretirana TAA (900 mg/kg, n=18); 3. grupa tretirana finasteridom, FIN (150 mg/kg, n=8); 4. FIN+TAA900 grupa (n=10) tretirana finasteridom (150 mg/kg) i TAA (900 mg/kg)...

Hepatic encephalopathy (HE) represents a neuropsychiatric syndrome, that appears as a consequence of acute or chronic liver failure. Various experimental models are used for the investigation of the pathogenesis of HE, including porto-caval shunt, portal vein stricture, models induced by hepatotoxic agents (thioacetamide, D-galactosamine, acetaminophen, azoxymethane, carbon tetrachloride) and models of liver cirrhosis. Hyperammonemia has a pivotal role in the development of HE, and mechanisms involved in the pathogenesis of HE include: cytotoxic brain edema, alterations in neurotransmission (especially glutamatergic and GABAergic), energy disturbances, oxidative stress, mitochondrial dysfunction and neuroinflammation. The synthesis of neurosteroids is increased in HE and by positive allosteric modulation of gamma-aminobutyric acid (GABAA) receptors they potentiate the effects og GABA in the central nervous system. Finasteride, 5α-reductase and neurosteroid synthesis inhibitor, may potentially modulate the course of HE. The aims of this dissertation were: to investigate the behavioral and electroencephalographic (EEG) changes in thioacetamide-induced HE in rats; to determine the parameters of oxidative stress and antioxidative protection, the activity of acetylcholinesterase (AchE) and cellular marker expression in various brain regions; to investigate the effects of finasteride on behavioral, EEG and cellular changes in thioacetamide-induced HE in rats. In order to investigate the effects of thioacetamide (TAA) on the behavior, EEG and cellular changes male Wistar rats were divided into the following groups: 1. control; 2. experimental group treated with TAA in a dose-dependent manner: TAA300 (300 mg/kg; n=8), TAA600 (600 mg/kg; n=10) and TAA900 (900 mg/kg; n=18). Daily doses of TAA (300 mg/kg) were administered once (TAA300), twice (TAA600) or three times (TAA900) in subsequent days. In order to investigate the effects of finasteride on TAA-induced HE, the animals were divided into the following groups: 1. control (n=8); 2. TAA900 group treated with TAA (900 mg/kg; n=18); 3. FIN group treated with finasteride (150 mg/kg; n=8); 4. FIN+TAA900 group (n=10) treated with FIN (150 mg/kg) and TAA (900 mg/kg)...