The ADP-responsive P2Y12 receptor is expressed on both platelets and microglia. Clinical data show that ticagrelor, a direct-acting, reversibly binding P2Y12-receptor antagonist, reduces total cardiovascular events, including stroke. In our present study, we investigated the expression of P2Y12 receptors and the effects of ticagrelor on brain injury in Sprague-Dawley rats subjected to a permanent middle cerebral artery occlusion (MCAo). Rats were treated per os with ticagrelor 3 mg/kg or vehicle at 10 minutes, 22, and 36 hours after MCAo and killed after 48 hours. Immunofluorescence analysis showed an ischemia-related modulation of the P2Y12 receptor, which is constitutively expressed in Iba1+ resting microglia. After MCAo, activated microglia was mainly concentrated around the lesion, with fewer cells present inside the ischemic core. Ticagrelor significantly attenuated the evolution of ischemic damage-evaluated by magnetic resonance imaging (MRI) at 2, 24, and 48 hours after MCAo-, the number of infiltrating cells expressing the microglia/monocyte marker ED-1, the cerebral expression of proinflammatory mediators (interleukin 1 (IL-1), monocyte chemoattractant protein 1 (MCP-1), nitric oxide synthase (iNOS)) and the associated neurologic impairment. In transgenic fluorescent reporter CX3CR1-green fluorescent protein (GFP) mice, 72 hours after MCAo, ticagrelor markedly reduced GFP+ microglia and both early and late infiltrating blood-borne cells. Finally, in primary cultured microglia, ticagrelor fully inhibited ADP-induced chemotaxis (P<0.01). Our results show that ticagrelor is protective against ischemia-induced cerebral injury and this effect is mediated, at least partly, by inhibition of P2Y12-mediated microglia activation and chemotaxis.Journal of Cerebral Blood Flow & Metabolism advance online publication, 19 March 2014; doi:10.1038/jcbfm.2014.45.
Microglia is a key player in the reduction of stroke damage promoted by the new antithrombotic agent ticagrelor / P. Gelosa, D. Lecca, M. Fumagalli, D. Wypych, A. Pignieri, M. Cimino, C. Verderio, M. Enerbäck, E. Nikookhesal, E. Tremoli, M.P. Abbracchio, L. Sironi. - In: JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM. - ISSN 0271-678X. - 34:6(2014 Jun), pp. 979-988.
|Titolo:||Microglia is a key player in the reduction of stroke damage promoted by the new antithrombotic agent ticagrelor|
GELOSA, PAOLO (Primo)
LECCA, DAVIDE (Secondo)
ABBRACCHIO, MARIA PIA (Penultimo)
SIRONI, LUIGI (Ultimo)
|Parole Chiave:||microglia ; middle cerebral artery occlusion ; P2Y12 receptor ; rat ; ticagrelor|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||giu-2014|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/jcbfm.2014.45|
|Appare nelle tipologie:||01 - Articolo su periodico|