Abstract
Finasteride (FIN) inhibits neurosteroid synthesis and potentially improves the course of hepatic encephalopathy (HE). This study aimed to investigate the effects of FIN on brain oxidative stress and acetylcholinesterase (AchE) activity in acute thioacetamide-induced HE in rats. Male Wistar rats were divided into groups: 1. control; 2. thioacetamide-treated group (TAA; 900 mg/kg); 3. finasteride-treated group (FIN; 150 mg/kg); 4. group treated with FIN and TAA (FIN+TAA). Daily doses of FIN (50 mg/kg) and TAA (300 mg/kg) were administered intraperitoneally during three days and in FIN+TAA group FIN was administered 2h before every dose of TAA. FIN pretreatment prevented TAA-induced rise in malondialdehyde level in the cortex due to restoration of catalase activity and increased expression of superoxide dismutase 1 (SOD1) and induced an increase in malondialdehyde level in the thalamus due to reduction of glutathione peroxidase (GPx) and glutathione reductase (GR) activity. Although FIN pretreatment did not affect malondialdehyde level in hippocampus and caudate nucleus, hippocampal SOD1 expression was higher (p<0.05) and GR activity lower in FIN+TAA vs. TAA group (p<0.05). GPx activity was lower in caudate nucleus in FIN+TAA vs. TAA group (p<0.01). FIN pretreatment prevented TAA-induced rise in AchE activity in the thalamus and caudate nucleus and AchE activity correlates inversely in the thalamus (p<0.05) and positively in caudate nucleus (p<0.01) with malondialdehyde level. FIN has regionally selective effects on oxidative stress and AchE activity in the brain in acute TAA-induced HE in rats. The prooxidant role of FIN in the thalamus may be causally linked with inhibition of AchE.
Highlights
Acute or chronic liver failure increase blood ammonia level, leading to the development of neuropsychiatric syndrome known as hepatic encephalopathy (HE) [1]
Blood ammonia concentration was significantly higher in the motor and EEG signs ofthioacetamide (TAA) (83.2 ± 10.3 μmol/L, p
While FIN alone reduced MDA level in the cortex (21.99 ± 4.02 nmol/mg prot., p
Summary
Acute or chronic liver failure increase blood ammonia level, leading to the development of neuropsychiatric syndrome known as hepatic encephalopathy (HE) [1]. Oxidative stress is closely interconnected with alterations in neurotransmission in the development of HE. Acute HE is associated with increased synaptic glutamate level [7], that induces neuronal Ca2+ influx due to activation of N-methyl-D-aspartate (NMDA) receptors, and results in mitochondrial permeability transition and increased reactive oxygen species (ROS) production [8,9]. Together with ROS reactive nitrogen species activate nuclear factor kappa B (NF-κB), a transcriptional regulator of inducible NOS (iNOS) gene [5,6], followed by increased production of NO and aggravation of oxidative stress. Other mechanisms of ROS generation include cell swelling [4,6], direct effect of ammonia [10] and effects of proinflammatory cytokines [11]
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