title: Sildenafil reduces neuroinflammation in cerebellum, restores GABAergic tone, and improves motor in-coordination in rats with hepatic encephalopathy.
abstract: OBJECTIVE
  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 GABAergic tone in cerebellum; (ii) increased GABAergic tone would be due to neuroinflammation; (iii) increasing cGMP would reduce neuroinflammation and GABAergic 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 GABAergic 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 GAT1 is reduced, while GAT3 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 GABAergic neurotransmission in impairing motor coordination in PCS rats.
authors.affiliation: Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Agusti
authors.affiliation: Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Hernández-Rabaza
authors.affiliation: Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Balzano
authors.affiliation: Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Lucas
authors.initials: L
authors.lastname: Taoro-Gonzalez
authors.affiliation: Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ibañez-Grau
authors.affiliation: Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cabrera-Pastor
authors.affiliation: Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Santos
authors.initials: S
authors.lastname: Fustero
authors.affiliation: Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Llansola
authors.affiliation: Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Carmina
authors.initials: C
authors.lastname: Montoliu
authors.affiliation: Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Vicente
authors.identifier: http://orcid.org/0000-0003-3145-9538
authors.initials: V
authors.lastname: Felipo
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D002531:Cerebellum / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D053583:Interleukin-1beta / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009048:Motor Skills / Q000187:drug effects* / Q000502:physiology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D017208:Rats, Wistar; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D050485:GABA Plasma Membrane Transport Proteins; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; C493417:Slc6a11 protein, rat; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D005680:gamma-Aminobutyric Acid; D000068677:Sildenafil Citrate
keywords: GABAergic neurotransmission; GAT3; cGMP, neuroinflammation; hepatic encephalopathy; sildenafil