Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE) with mild cognitive impairment. Hyperammonemia is a main contributor to cognitive impairment in MHE, which is mediated by neuroinflammation. GABAergic neurotransmission is altered in hyperammonemic rats. We hypothesized that, in hyperammonemic rats, (a) enhanced GABAergic tone would contribute to induce neuroinflammation, which would be improved by reducing GABAergic tone by chronic bicuculline treatment; (b) this would improve spatial learning and memory impairment; and (c) modulation of glutamatergic neurotransmission would mediate this cognitive improvement. The aim of this work was to assess the above hypotheses. Bicuculline was administrated intraperitoneally once a day for 4 weeks to control and hyperammonemic rats. The effects of bicuculline on microglia and astrocyte activation, IL-1β content, on membrane expression of AMPA and NMDA glutamate receptors subunits in the hippocampus and on spatial learning and memory as well as anxiety were assessed. Treatment with bicuculline reduces astrocyte activation and IL-1β but not microglia activation in the hippocampus of hyperammonemic rats. Bicuculline reverses the changes in membrane expression of AMPA receptor subunits GluA1 and GluA2 and of the NR2B (but not NR1 and NR2A) subunit of NMDA receptors. Bicuculline improves spatial learning and working memory and decreases anxiety in hyperammonemic rats. In hyperammonemia, enhanced activation of GABA A receptors in the hippocampus contributes to some but not all aspects of neuroinflammation, to altered glutamatergic neurotransmission and to impairment of spatial learning and memory as well as anxiety, all of which are reversed by reducing activation of GABA A receptors with bicuculline.

No abstract

Alcohol consumption during pregnancy damages the central nervous system of developing fetus and results in persistent physical and neurobehavioral abnormalities, including learning and memory disorders. The hippocampus which is involved in learning and memory is highly susceptible to the ethanol neurotoxic effects. Oxidative stress is one of the mechanisms in alcoholinduced disorders. Ethanol also interferes with the brain-derived neurotrophic factors (BDNF) expression. Using vitamin E as a potent antioxidant, we studied the possible interrelation between oxidative stress and BDNF on cognition.Ethanol (4 g/kg) and vitamin E (100, 200, and 400 mg/kg) were given to pregnant Wistar rats on first day of gestation (GD) until weaning (28 days).Oxidative stress marker, BDNF expression, and cyclic AMP-response bindingprotein (CREB) expression levels were measured on postnatal days (PND) 28. Object location memory (OLM) was evaluated on PND 34. Our results demonstrated that ethanol exposure significantly reduced glutathione peroxidase (GPx) activity, reduced glutathione (GSH), reduced/oxidized glutathione (GSH/GSSG) ratio, and increased superoxide dismutase (SOD) activity, malondialdehyde (MDA) levels, and carbonyl protein content in the hippocampus. Total BDNF, BDNF mRNA, and CREB expression significantly reduced in the hippocampus by ethanol exposure. Also, ethanol significantly reduced the discrimination index (DI) in the OLM test. In addition, vitamin E administration could reduce oxidative stress, increase significantly BDNF and CREB levels, and improve cognitive dysfunction induced by ethanol exposure. Collectively, results suggest that probably oxidative stress can interrelate with the BDNF system for modulating cognitive function in the ethanol-exposed rat.