title: Purinergic receptor P2RY12-dependent microglial closure of the injured blood-brain barrier.
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.
authors.affiliation: Center for Translational Neuromedicine, University of Rochester Medical School, Rochester, NY 14642;
authors.forename: Nanhong
authors.initials: N
authors.lastname: Lou
authors.affiliation: Center for Translational Neuromedicine, University of Rochester Medical School, Rochester, NY 14642;
authors.forename: Takahiro
authors.initials: T
authors.lastname: Takano
authors.affiliation: Center for Translational Neuromedicine, University of Rochester Medical School, Rochester, NY 14642;
authors.forename: Yong
authors.initials: Y
authors.lastname: Pei
authors.affiliation: Center for Translational Neuromedicine, University of Rochester Medical School, Rochester, NY 14642;
authors.forename: Anna L
authors.initials: AL
authors.lastname: Xavier
authors.affiliation: 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.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Goldman
authors.affiliation: 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.
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D002465:Cell Movement; D000077144:Clopidogrel; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D058925:Receptors, Purinergic P2Y12 / Q000502:physiology*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C548577:P2ry12 protein, mouse; D010975:Platelet Aggregation Inhibitors; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: blood–brain barrier; clopidogrel; microglia; purinergic receptors; stroke