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Microglia is a key player in the reduction of stroke damage promoted by the new antithrombotic agent ticagrelor.

Abstract
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.
AuthorsPaolo Gelosa, Davide Lecca, Marta Fumagalli, Dorota Wypych, Alice Pignieri, Mauro Cimino, Claudia Verderio, Malin Enerbäck, Elham Nikookhesal, Elena Tremoli, Maria P Abbracchio, Luigi Sironi
JournalJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 34 Issue 6 Pg. 979-88 (Jun 2014) ISSN: 1559-7016 [Electronic] United States
PMID24643079 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Ccl2 protein, mouse
  • Ccl2 protein, rat
  • Chemokine CCL2
  • Ectodysplasins
  • Eda protein, mouse
  • Fibrinolytic Agents
  • Interleukin-1
  • Nerve Tissue Proteins
  • Purinergic P2Y Receptor Antagonists
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Nos2 protein, rat
  • Ticagrelor
  • Adenosine
Topics
  • Adenosine (analogs & derivatives, pharmacology)
  • Animals
  • Brain Ischemia (drug therapy, genetics, metabolism, pathology, physiopathology)
  • Chemokine CCL2 (biosynthesis)
  • Ectodysplasins (biosynthesis)
  • Fibrinolytic Agents (pharmacology)
  • Interleukin-1 (biosynthesis)
  • Mice
  • Mice, Transgenic
  • Microglia (metabolism, pathology)
  • Nerve Tissue Proteins (biosynthesis, genetics)
  • Nitric Oxide Synthase Type II (biosynthesis, genetics)
  • Purinergic P2Y Receptor Antagonists (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Stroke (drug therapy, genetics, metabolism, pathology, physiopathology)
  • Time Factors

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