Enhanced Activation of the S1PR2-IL-1ß-Src-BDNF-TrkB Pathway Mediates Neuroinflammation in the Hippocampus and Cognitive Impairment in Hyperammonemic Rats.

Fecha de publicación: 08/12/2023

Autores de CIPF

María Sancho Alonso

Autor
Yaiza Arenas Ortiz

Autor
Paula Izquierdo Altarejos

Autor
Marta Llansola Gil

Autor
Vicente Felipo Orts

Autor

Participantes ajenos a CIPF

Martinez-Garcia M

Grupos de Investigación

Laboratorio de Neurobiología

Jefe/a de Grupo

Vicente Felipo Orts

Abstract

Hyperammonemia contributes to hepatic encephalopathy. In hyperammonemic rats, cognitive function is impaired by altered glutamatergic neurotransmission induced by neuroinflammation. The underlying mechanisms remain unclear. Enhanced sphingosine-1-phosphate receptor 2 (S1PR2) activation in the cerebellum of hyperammonemic rats contributes to neuroinflammation. in In hyperammonemic rats, we assessed if blocking S1PR2 reduced hippocampal neuroinflammation and reversed cognitive impairment and if the signaling pathways were involved. S1PR2 was blocked with intracerebral JTE-013, and cognitive function was evaluated. The signaling pathways inducing neuroinflammation and altered glutamate receptors were analyzed in hippocampal slices. JTE-013 improved cognitive function in the hyperammonemic rats, and hyperammonemia increased S1P. This increased IL-1ß, which enhanced Src activity, increased CCL2, activated microglia and increased the membrane expression of the NMDA receptor subunit GLUN2B. This increased p38-MAPK activity, which altered the membrane expression of AMPA receptor subunits and increased BDNF, which activated the TrkB ? PI3K ? Akt ? CREB pathway, inducing sustained neuroinflammation. This report unveils key pathways involved in the induction and maintenance of neuroinflammation in the hippocampus of hyperammonemic rats and supports S1PR2 as a therapeutic target for cognitive impairment.

Datos de la publicación

ISSN/ISSNe:: 1422-0067, 1422-0067
Tipo:: Article
Páginas:: -
DOI:: 10.3390/ijms242417251
PubMed:: 38139078

Documentos

No hay documentos

Métricas

Filiaciones

Sancho-Alonso M:: Laboratory of Neurobiology, Centro de Investigación Principe Felipe, 46012 Valencia, Spain

Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain

Systems Neuropharmacology Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain

Biomedical Research Networking Center for Mental Health (CIBERSAM), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain
Arenas YM:: Laboratory of Neurobiology, Centro de Investigación Principe Felipe, 46012 Valencia, Spain
Izquierdo-Altarejos P:: Laboratory of Neurobiology, Centro de Investigación Principe Felipe, 46012 Valencia, Spain
Martinez-Garcia M:: Laboratory of Neurobiology, Centro de Investigación Principe Felipe, 46012 Valencia, Spain
Llansola M:: Laboratory of Neurobiology, Centro de Investigación Principe Felipe, 46012 Valencia, Spain
Felipo V:: Laboratory of Neurobiology, Centro de Investigación Principe Felipe, 46012 Valencia, Spain

Keywords

BDNF, cognitive impairment, glutamate receptor, hepatic encephalopathy, neuroinflammation, sphingosine-1-phosphate

Campos de Estudio

Proyectos asociados

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

Investigador Principal: VICENTE FELIPO ORTS

MINISTERIO DE CIENCIA, INNOVACION Y UNIVERSIDADES . 2021

Molecular mechanisms of the neurological (cognitive and motor) alterations in hyperammonemia and hepatic encephalopathy. Therapeutic implications.