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  3. Peripheral inflammation induces neuroinflammation that alters neurotransmission and cognitive and motor function in hepatic encephalopathy: Underlying mechanisms and therapeutic implications

Peripheral inflammation induces neuroinflammation that alters neurotransmission and cognitive and motor function in hepatic encephalopathy: Underlying mechanisms and therapeutic implications

Fecha de publicación:

Autores de CIPF

Participantes ajenos a CIPF

  • García-García R
  • Mangas-Losada A
  • Izquierdo-Altarejos P

Grupos de Investigación

Abstract

Several million patients with liver cirrhosis suffer minimal hepatic encephalopathy (MHE), with mild cognitive and coordination impairments that reduce their quality of life and life span. Hyperammonaemia and peripheral inflammation act synergistically to induce these neurological alterations. We propose that MHE appearance is because of the changes in peripheral immune system, which are transmitted to brain, leading to neuroinflammation that alters neurotransmission leading to cognitive and motor alterations. We summarize studies showing that MHE in cirrhotic patients is associated with alterations in the immune system and that patients died with HE show neuroinflammation in cerebellum, with microglial and astrocytic activation and Purkinje cell loss. We also summarize studies in animal models of MHE on the role of peripheral inflammation in neuroinflammation induction, how neuroinflammation alters neurotransmission and how this leads to cognitive and motor alterations. These studies identify therapeutic targets and treatments that improve cognitive and motor function. Rats with MHE show neuroinflammation in hippocampus and altered NMDA and AMPA receptor membrane expression, which impairs spatial learning and memory. Neuroinflammation in cerebellum is associated with altered GABA transporters and extracellular GABA, which impair motor coordination and learning in a Y maze. These alterations are reversed by treatments that reduce peripheral inflammation (anti-TNF, ibuprofen), neuroinflammation (sulphoraphane, p38 inhibitors), GABAergic tone (bicuculline, pregnenolone sulphate) or increase extracellular cGMP (sildenafil or cGMP). The mechanisms identified would also occur in other chronic diseases associated with inflammation, aging and some mental and neurodegenerative diseases. Treatments that improve MHE may also be beneficial to treat these pathologies.

Datos de la publicación

ISSN/ISSNe:
1748-1708, 1748-1716

Acta Physiologica  WILEY

Tipo:
Review
Páginas:
-
PubMed:
30830722

Citas Recibidas en Web of Science: 98

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Keywords

  • cognitive function; hepatic encephalopathy; hyperammonaemia; neuroinflammation; neurotransmission; peripheral inflammation

Proyectos asociados

Red de Transtornos Adictivos

Investigador Principal: CONSUELO GUERRI SIRERA

INSTITUTO DE SALUD CARLOS III . 2017

Bases moleculares de las alteraciones neurológicas (cognitivas y motoras) en hiperamonemia y encefalopatía hepática. Implicaciones terapéuticas

Investigador Principal: VICENTE FELIPO ORTS

MINISTERIO DE ECON. Y COMPET. . 2018

Mecanismos moleculares y cerebrales de las alteraciones cognitivas y motoras en hiperamonemia y encefalopatía hepática. Implicaciones terapeúticas y diagnósticas

Investigador Principal: VICENTE FELIPO ORTS

CONSELLERIA DE EDUCACION . 2018

Identification and modelling of molecular and cellular events of the inmune response associated to the appearence of minimal hepatic encephalopaty in cirrhotic patients

Investigador Principal: VICENTE FELIPO ORTS

FUNDACION RAMON ARECES . 2019

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