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 (P12-mediated microglia activation and chemotaxis.
| Original language | English |
|---|---|
| Pages (from-to) | 979-988 |
| Number of pages | 10 |
| Journal | Journal of Cerebral Blood Flow and Metabolism |
| Volume | 34 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 2014 |
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Keywords
- microglia
- middle cerebral artery occlusion
- rat
- ticagrelor
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Clinical Neurology
- Neurology
Cite this
Microglia is a key player in the reduction of stroke damage promoted by the new antithrombotic agent ticagrelor. / Gelosa, Paolo; Lecca, Davide; Fumagalli, Marta; Wypych, Dorota; Pignieri, Alice; Cimino, Mauro; Verderio, Claudia; Enerbäck, Malin; Nikookhesal, Elham; Tremoli, Elena; Abbracchio, Maria P.; Sironi, Luigi.
In: Journal of Cerebral Blood Flow and Metabolism, Vol. 34, No. 6, 2014, p. 979-988.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Microglia is a key player in the reduction of stroke damage promoted by the new antithrombotic agent ticagrelor
AU - Gelosa, Paolo
AU - Lecca, Davide
AU - Fumagalli, Marta
AU - Wypych, Dorota
AU - Pignieri, Alice
AU - Cimino, Mauro
AU - Verderio, Claudia
AU - Enerbäck, Malin
AU - Nikookhesal, Elham
AU - Tremoli, Elena
AU - Abbracchio, Maria P.
AU - Sironi, Luigi
PY - 2014
Y1 - 2014
N2 - 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 (P12-mediated microglia activation and chemotaxis.
AB - 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 (P12-mediated microglia activation and chemotaxis.
KW - microglia
KW - middle cerebral artery occlusion
KW - rat
KW - ticagrelor
UR - http://www.scopus.com/inward/record.url?scp=84901829182&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84901829182&partnerID=8YFLogxK
U2 - 10.1038/jcbfm.2014.45
DO - 10.1038/jcbfm.2014.45
M3 - Article
C2 - 24643079
AN - SCOPUS:84901829182
VL - 34
SP - 979
EP - 988
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
SN - 0271-678X
IS - 6
ER -