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.

• Authors: Paolo Gelosa, Davide Lecca, Marta Fumagalli, Dorota Wypych, Alice Pignieri, Mauro Cimino, Claudia Verderio, Malin Enerbäck, Elham Nikookhesal, Elena Tremoli, Maria P Abbracchio, Luigi Sironi
• Journal: Journal 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
• PMID: 24643079 (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)
• Ticagrelor
• Time Factors