Open AccessSildenafil reduces neuroinflammation in cerebellum, restores GABA ergic tone, and improves motor in‐coordination in rats with hepatic encephalopathy
Author(s) -
Agusti Ana,
HernándezRabaza Vicente,
Balzano Tiziano,
TaoroGonzalez Lucas,
IbañezGrau Andrea,
CabreraPastor Andrea,
Fustero Santos,
Llansola Marta,
Montoliu Carmina,
Felipo Vicente
Publication year - 2017
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12688
Subject(s) - neuroinflammation , motor coordination , microglia , neuroscience , cerebellum , excitotoxicity , chemistry , glutamate receptor , medicine , pharmacology , psychology , receptor , inflammation
Summary Aims Patients with liver disease may develop hepatic encephalopathy ( HE ), with cognitive impairment and motor in‐coordination. Rats with HE due to portacaval shunts ( PCS ) show motor in‐coordination. We hypothesized that in PCS rats: (i) Motor in‐coordination would be due to enhanced GABA ergic tone in cerebellum; (ii) increased GABA ergic tone would be due to neuroinflammation; (iii) increasing cGMP would reduce neuroinflammation and GABA ergic tone and restore motor coordination. To assess these hypotheses, we assessed if (i) treatment with sildenafil reduces neuroinflammation; (ii) reduced neuroinflammation is associated with reduced GABA ergic tone and restored motor coordination. Methods Rats were treated with sildenafil to increase cGMP . Microglia and astrocytes activation were analyzed by immunohistochemistry, extracellular GABA by microdialysis, and motor coordination in the beam walking. Results PCS rats show neuroinflammation in cerebellum, with microglia and astrocytes activation, increased IL ‐1b and TNF ‐a and reduced YM ‐1 and IL ‐4. Membrane expression of the GABA transporter GAT 1 is reduced, while GAT 3 is increased. Extracellular GABA and motor in‐coordination are increased. Sildenafil treatment eliminates neuroinflammation, microglia and astrocytes activation; changes in membrane expression of GABA transporters; and restores motor coordination. Conclusions This study supports an interplay between cGMP ‐neuroinflammation and GABA ergic neurotransmission in impairing motor coordination in PCS rats.