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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.00132


Michele Malaguarnera1,  MARTA LLANSOLA1, Tiziano Balzano1, Belen Gomez-Gimenez1, Carles Antunez-Muñoz1, Nuria Martinez-Alarcon1, Rahebeh Mahdinia2 and  Vicente Felipo1*
  • 1Centro de Investigacion Principe Felipe (CIPF), Spain
  • 2Damghan University, Iran

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; 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 astrocytes activation, IL-1β content, on membrane expression of AMPA and NMDA glutamate receptors subunits in hippocampus and on spatial learning and memory and anxiety were assessed.
Treatment with bicuculline reduces astrocyte activation and IL-1 but not microglia activation in hippocampus of hyperammonemic rats. Bicuculline reverses the changes in membrane expression of AMPA receptor subunits GluA1 and GluA2 and of 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 hippocampus contributes to some but not all aspects of neuroinflammation, to altered glutamatergic neurotransmission and to impairment of spatial learning and memory and anxiety, which are reversed by reducing activation of GABAA receptors with bicuculline

Keywords: Hyperammonemia, Neuroinflammation, Hippocampus, GABAA receptor, glutamate receptors, Hepatic Encephalopathy, Spatial learning, Anxiety, Astrocytes activation, IL-1b

Received: 18 Nov 2018; Accepted: 05 Feb 2019.

Edited by:

Morena Zusso, University of Padova, Italy

Reviewed by:

Hiroki Toyoda, Osaka University, Japan
Georgina Rodríguez De Lores Arnaiz, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina  

Copyright: © 2019 Malaguarnera, LLANSOLA, Balzano, Gomez-Gimenez, Antunez-Muñoz, Martinez-Alarcon, Mahdinia and Felipo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Vicente Felipo, Centro de Investigacion Principe Felipe (CIPF), Valencia, Spain,