Sildenafil reduces neuroinflammation in cerebellum, restores GABAergic tone, and improves motor in-coordination in rats with hepatic encephalopathy

Autores de CIPF

• Ana Agustí Feliu

  Autor

• Vicente Hernandez Rabaza

  Autor

• Tiziano Balzano

  Autor

• Lucas Taoro González

  Autor

• Andrea Cabrera Pastor

  Autor

• Santos Fustero Lardies

  Autor

• 

  Marta Llansola Gil

  Autor

• Carmina Montoliu Felix

  Autor

• 

  Vicente Felipo Orts

  Autor

Participantes ajenos a CIPF

• Ibanez-Grau, A

Grupos de Investigación

• Laboratorio de Neurobiología

  

  Jefe/a de Grupo

  Vicente Felipo Orts

• Unidad Mixta CIPF-INCLIVA de Deterioro Neurológico

Abstract

AimsPatients 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. MethodsRats 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. ResultsPCS 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. ConclusionsThis study supports an interplay between cGMP-neuroinflammation and GABAergic neurotransmission in impairing motor coordination in PCS rats.

Keywords

• cGMP; neuroinflammation; GABAergic neurotransmission; GAT3; hepatic encephalopathy; sildenafil