Abstract
Objective: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome caused by liver failure and by an impaired neurotransmission and neurological function caused by hyperammonemia (HA). HE, in turn, decreases the phosphorylation of protein kinase C epsilon (PKCε), contributing to the impairment of neuronal functions. Dehydroepiandrosterone (DHEA) exerts a neuroprotective effect by increasing the GABAergic tone through GABAA receptor stimulation. Therefore, we investigated the protective effect of DHEA in an animal model of HE, and the possible modulation of PKCε expression in different brain area.Methods: Fulminant hepatic failure was induced in 18 male, Sprague–Dawley rats by i.p. administration of 3 g/kg D-galactosamine, and after 30 min, a group of animals received a subcutaneous injection of 25 mg/kg (DHEA) repeated twice a day (3 days). Exploratory behavior and general activity were evaluated 24 h and 48 h after the treatments by the open field test. Then, brain cortex and cerebellum were used for immunoblotting analysis of PKCε level.Results: DHEA administration showed a significant improvement of locomotor activity both 24 and 48 h after D-galactosamine treatment (****p < 0.0001) but did not ameliorate liver parenchymal degeneration. Western blot analysis revealed a reduced immunoreactivity of PKCε (*p < 0.05) following D-galactosamine treatment in rat cortex and cerebellum. After the addition of DHEA, PKCε increased in the cortex in comparison with the D-galactosamine-treated (***p < 0.001) and control group (*p < 0.05), but decreased in the cerebellum (*p < 0.05) with respect to the control group. PKCε decreased after treatment with NH4Cl alone and in combination with DHEA in both cerebellum and cortex (****p < 0.0001). MTS assay demonstrated the synergistic neurotoxic action of NH4Cl and glutamate pretreatment in cerebellum and cortex along with an increased cell survival after DHEA pretreatment, which was significant only in the cerebellum (*p < 0.05).Conclusion: An association between the DHEA-mediated increase of PKCε expression and the improvement of comatose symptoms was observed. PKCε activation and expression in the brain could inhibit GABA-ergic tone counteracting HE symptoms. In addition, DHEA seemed to ameliorate the symptoms of HE and to increase the expression of PKCε in cortex and cerebellum.
Highlights
Hepatic encephalopathy (HE) is a reversible neuropsychiatric syndrome characterized by an impaired brain function that generally occurs in patients suffering from chronic liver disease or acute liver failure [1, 2]
In the evaluation of horizontal activity following the open field test, the groups of animals treated with D-galactosamine alone and treated with D-galactosamine + DHEA showed a significant reduction of the total distance traveled at both 24 and 48 h (∗∗∗∗p < 0.0001) when compared with the control group (Figure 1)
The animals treated with D-galactosamine + DHEA showed a significant increase of the total distance traveled at both times 24 and 48 h (∗∗∗∗p < 0.0001) in comparison with those treated with the D-galactosamine alone (Figure 1A)
Summary
Hepatic encephalopathy (HE) is a reversible neuropsychiatric syndrome characterized by an impaired brain function that generally occurs in patients suffering from chronic liver disease or acute liver failure [1, 2]. One of the main contributors to the alteration in neurotransmission and neurological function in HE is hyperammonemia [1, 8] In this sense, blood ammonia increase following impaired liver function can cause muscle wasting, neuronal electric activity, and astrocyte swelling [1, 9,10,11,12]. Due to an increased intracellular osmolarity caused by impaired ammonia metabolism and glutamine production, is supposed to be one of the possible explanations of brain edema that generally characterizes HE [11, 13]
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