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Proc Natl Acad Sci U S A. 2016 Jan 26;113(4):1074-9. doi: 10.1073/pnas.1520398113. Epub 2016 Jan 11.

Purinergic receptor P2RY12-dependent microglial closure of the injured blood-brain barrier.

Author information

1
Center for Translational Neuromedicine, University of Rochester Medical School, Rochester, NY 14642;
2
Center for Translational Neuromedicine, University of Rochester Medical School, Rochester, NY 14642; Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
3
Center for Translational Neuromedicine, University of Rochester Medical School, Rochester, NY 14642; Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark nedergaard@urmc.rochester.edu.

Abstract

Microglia are integral functional elements of the central nervous system, but the contribution of these cells to the structural integrity of the neurovascular unit has not hitherto been assessed. We show here that following blood-brain barrier (BBB) breakdown, P2RY12 (purinergic receptor P2Y, G-protein coupled, 12)-mediated chemotaxis of microglia processes is required for the rapid closure of the BBB. Mice treated with the P2RY12 inhibitor clopidogrel, as well as those in which P2RY12 was genetically ablated, exhibited significantly diminished movement of juxtavascular microglial processes and failed to close laser-induced openings of the BBB. Thus, microglial cells play a previously unrecognized protective role in the maintenance of BBB integrity following cerebrovascular damage. Because clopidogrel antagonizes the platelet P2Y12 receptor, it is widely prescribed for patients with coronary artery and cerebrovascular disease. As such, these observations suggest the need for caution in the postincident continuation of P2RY12-targeted platelet inhibition.

KEYWORDS:

blood–brain barrier; clopidogrel; microglia; purinergic receptors; stroke

Comment in

PMID:
26755608
PMCID:
PMC4743790
DOI:
10.1073/pnas.1520398113
[Indexed for MEDLINE]
Free PMC Article

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