Abstract
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 GABAA 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 GABAA receptors with bicuculline.
Highlights
Patients with liver cirrhosis may develop covert or minimal hepatic encephalopathy (MHE) with mild cognitive impairment, attention deficits and psychomotor slowing, which impair quality of life, reduce life span and increase accidents, falls and hospitalizations
Animals were distributed into four groups: control with vehicle (CV); control treated with bicuculline (CB); hyperammonemic rats (HA); hyperammonemic rats treated with bicuculline (HB)
Hyperammonemic rats show activated microglia in the hippocampus, with a less ramified and more ameboid morphology reflected in a reduction (p < 0.05) of the perimeter to 280 ± 8 μm compared to 315 ± 9 μm in control rats (Figure 2)
Summary
Patients with liver cirrhosis may develop covert or MHE with mild cognitive impairment, attention deficits and psychomotor slowing, which impair quality of life, reduce life span and increase accidents, falls and hospitalizations. Hyperammonemia and peripheral inflammation play synergistic roles in inducing the cognitive and motor alterations in MHE (Shawcross et al, 2004; Montoliu et al, 2009; Felipo et al, 2012). Hyperammonemic rats show neuroinflammation in the hippocampus that is associated with altered membrane expression of glutamate receptors and impaired spatial learning and memory (Cabrera-Pastor et al, 2016). These alterations are reversed by treating the rats with sulforaphane, which reduces neuroinflammation in the hippocampus (Hernández-Rabaza et al, 2016)
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