GPR17, a previously orphan G protein-coupled receptor, can be activated by both uracil nucleotides and cysteinyl-leukotrienes, two chemically and structurally unrelated families of ligands, released in large amount after brain injury. In vivo inhibition of GPR17 reduces ischemic damage in a rat focal ischemia model, suggesting GPR17 as a molecular target mediating brain damage under pathological conditions. However, we have demonstrated that GPR17 is a sensor of damage rather than a receptor of death. In mouse intact brain, GPR17 is expressed at low levels by cortical neurons and at higher extent by a subset of oligodendrocyte precursor cells (OPCs) may play important roles in maintaining nervous system integrity and promoting its repair after various kind of insults. After ischemia, induced by Middle Cerebral Artery occlusion (MCAo), the expression pattern of GPR17 is finely regulated. Early (24 h) after ischemia, the receptor was induced in several neurons within the infarct area. After 48h, a significant up-regulation was visible in the ischemic penumbra: some of these cells were also positive for the stress marker HSP70. Moreover, 3 days after MCAo, GPR17 was found on activated microglia/macrophages migrating to the lesioned area, whereas the number of proliferating GPR17+ OPCs was increased in both the penumbra area and ipsilateral striatum. This increase suggests that GPR17 may also be involved in the responses to demyelination following an ischemic event. To confirm a possible role in myelination, we demonstrated that in vitro treatments with GPR17 agonists promote cell differentiation toward mature oligodendrocytes. We conclude that GPR17 can both contribute to damage propagation and participate to its repair depending upon specific post-injury stages. Thus, the manipulation of GPR17 may foster neuro-reparative responses to damage and favour functional recovery not only in stroke, but also after neurodegenerative diseases characterized by oligodendroglial damage such as multiple sclerosis.
The P2Y-like receptor GPR17 as a sensor of damage and a target of CNS repair / D. Lecca, P. Gelosa, M. Fumagalli, G. Villa, C. Verderio, P. Rosa, L. Sironi, E. Tremoli, M. Cimino, M.P. Abbracchio. ((Intervento presentato al convegno Next Step : la giovane ricerca avanza tenutosi a Milano nel 2010.
|Titolo:||The P2Y-like receptor GPR17 as a sensor of damage and a target of CNS repair|
LECCA, DAVIDE (Primo)
GELOSA, PAOLO (Secondo)
ABBRACCHIO, MARIA PIA (Ultimo)
|Data di pubblicazione:||1-lug-2010|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Citazione:||The P2Y-like receptor GPR17 as a sensor of damage and a target of CNS repair / D. Lecca, P. Gelosa, M. Fumagalli, G. Villa, C. Verderio, P. Rosa, L. Sironi, E. Tremoli, M. Cimino, M.P. Abbracchio. ((Intervento presentato al convegno Next Step : la giovane ricerca avanza tenutosi a Milano nel 2010.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|