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

Abstract

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 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: Ana Agusti, Vicente Hernández-Rabaza, Tiziano Balzano, Lucas Taoro-Gonzalez, Andrea Ibañez-Grau, Andrea Cabrera-Pastor, Santos Fustero, Marta Llansola, Carmina Montoliu, Vicente Felipo
• Journal: CNS neuroscience & therapeutics (CNS Neurosci Ther) Vol. 23 Issue 5 Pg. 386-394 (May 2017) ISSN: 1755-5949 [Electronic] England
• PMID: 28296282 (Publication Type: Journal Article)
• Copyright: © 2017 John Wiley & Sons Ltd.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• GABA Plasma Membrane Transport Proteins
• IL1B protein, rat
• Interleukin-1beta
• Slc6a11 protein, rat
• Tumor Necrosis Factor-alpha
• Interleukin-4
• gamma-Aminobutyric Acid
• Sildenafil Citrate

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Astrocytes (drug effects, pathology, physiology)
• Cerebellum (drug effects, immunology, pathology)
• Disease Models, Animal
• GABA Plasma Membrane Transport Proteins (metabolism)
• Hepatic Encephalopathy (drug therapy, pathology, physiopathology)
• Interleukin-1beta (metabolism)
• Interleukin-4 (metabolism)
• Male
• Microglia (drug effects, pathology, physiology)
• Motor Skills (drug effects, physiology)
• Neuroimmunomodulation (drug effects, physiology)
• Rats, Wistar
• Sildenafil Citrate (pharmacology)
• Tumor Necrosis Factor-alpha (metabolism)
• gamma-Aminobutyric Acid (metabolism)