Finasteride improves motor, EEG, and cellular changes in rat brain in thioacetamide-induced hepatic encephalopathy

Abstract

(HE). This study evaluated the effects of finasteride, inhibitor of neurosteroid synthesis, on motor, EEG, and cellular changes in rat brain in thioacetamide-induced HE. Male Wistar rats were divided into the following groups: 1) control; 2) thioacetamide-treated group, TAA (300 mg·kg Ϫ1 ·day Ϫ1 ); 3) finasteride-treated group, FIN (50 mg·kg Ϫ1 ·day Ϫ1 ); and 4) group treated with FIN and TAA (FIN ϩ TAA). Daily doses of TAA and FIN were administered in three subsequent days intraperitoneally, and in the FIN ϩ TAA group FIN was administered 2 h before every dose of TAA. Motor and reflex activity was determined at 0, 2, 4, 6, and 24 h, whereas EEG activity was registered about 24 h after treatment. The expressions of neuronal (NeuN), astrocytic [glial fibrilary acidic protein (GFAP)], microglial (Iba1), and oligodendrocyte (myelin oligodendrocyte glycoprotein) marker were determined 24 h after treatment. While TAA decreased all tests, FIN pretreatment (FIN ϩ TAA) significantly improved equilibrium, placement test, auditory startle, head shake reflex, motor activity, and exploratory behavior vs. the TAA group. Vital reflexes (withdrawal, grasping, righting and corneal reflex) together with mean EEG voltage were significantly higher (P Ͻ 0.01) in the FIN ϩ TAA vs. the TAA group. Hippocampal NeuN expression was significantly lower in TAA vs. control (P Ͻ 0.05). Cortical Iba1 expression was significantly higher in experimental groups vs. control (P Ͻ 0.05), whereas hippocampal GFAP expression was increased in TAA and decreased in the FIN ϩ TAA group vs. control (P Ͻ 0.05). Finasteride improves motor and EEG changes in TAA-induced HE and completely prevents the development of hepatic coma. motor tests; electroencephalography; cellular markers HEPATIC ENCEPHALOPATHY (HE) represents a clinical syndrome characterized by neurological and psychiatric disturbances that develop as a result of acute or chronic liver failure (21). Various mechanisms are involved in the pathogenesis of HE, including changes in neurotransmission (17), oxidative stress, bioenergetic failure, mitochondrial permeability transition (49), inflammatory response, and immune dysfunction (14, 52), due to accumulation of various toxins in the organism, principally ammonia (4).Changes in glutamatergic and GABAergic transmission have an important role in the development of HE (13, 16). Both acute and chronic liver failure were found to be associated with increased GABAergic activity due to increased neurosteroid synthesis. Neurosteroids are steroid compounds, synthesized in mitochondria of glial cells and neurons from cholestrol (2). Cholesterol is taken up into mitochondria via the activation of translocator protein (TSPO), a multimeric complex that spans both outer and inner mitochondrial membrane. Ammonia and manganese, toxins accumulated in HE, and proinflammatory cytokines upregulate components of TSPO and increase cholesterol uptake into the mitochondrion (2, 4). Cholesterol serves as a substrate for increased synthesis of neurosteroids, including all...

Neurotoxicity of Ammonia

“…The TSPO is strongly upregulated in animal models of hyperammonemia and in patients with hepatic encephalopathy [87][88][89][90][91], which then increases neurosteroid levels [92,93]. These interesting observations await for translation to clinical trials, particularly as finasteride has alleviated various symptoms in a model of thioacetamide-induced hepatic encephalopathy in rats [94].…”

Sex hormones modulate pathogenic processes in experimental traumatic brain injury

“…This may also have an impact on the interpretation of results showing neuroprotective effects of FIN (Mladenovic et al . ; Tanaka et al . ).…”

The effect of finasteride on anxiety in rats

“…Finasterid (FIN), inhibitor 5α-reduktaze, primenjuje se u terapiji hiperplazije prostate (10) i androgene alopecije (11). Ovaj inhibitor smanjuje unos etanola kod miševa kod kojih se razvila zavisnost (12), izaziva hiperalgeziju (13), deluje proepileptogeno (14, 15) i poboljšava tok hepatične encefalopatije (HE) (16). Blokadom 5α-reduktaze u mozgu FIN inhibira sintezu ALLO i THDOC i preusmerava progesteron u alternativne metaboličke puteve, čime menja GABA-ergičku transmisiju.…”