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Microglial P2Y12 deficiency/inhibition protects against brain ischemia.
- Source :
-
PloS one [PLoS One] 2013 Aug 05; Vol. 8 (8), pp. e70927. Date of Electronic Publication: 2013 Aug 05 (Print Publication: 2013). - Publication Year :
- 2013
-
Abstract
- Objective: Microglia are among the first immune cells to respond to ischemic insults. Triggering of this inflammatory response may involve the microglial purinergic GPCR, P2Y12, activation via extracellular release of nucleotides from injured cells. It is also the inhibitory target of the widely used antiplatelet drug, clopidogrel. Thus, inhibiting this GPCR in microglia should inhibit microglial mediated neurotoxicity following ischemic brain injury.<br />Methods: Experimental cerebral ischemia was induced, in vitro with oxygen-glucose deprivation (OGD), or in vivo via bilateral common carotid artery occlusion (BCCAO). Genetic knock-down in vitro via siRNA, or in vivo P2Y12 transgenic mice (P2Y12-/- or P2Y12+/-), or in vivo treatment with clopidogrel, were used to manipulate the receptor. Neuron death, microglial activation, and microglial migration were assessed.<br />Results: The addition of microglia to neuron-astrocyte cultures increases neurotoxicity following OGD, which is mitigated by microglial P2Y12 deficiency (P<0.05). Wildtype microglia form clusters around these neurons following injury, which is also prevented in P2Y12 deficient microglia (P<0.01). P2Y12 knock-out microglia migrated less than WT controls in response to OGD-conditioned neuronal supernatant. P2Y12 (+/-) or clopidogrel treated mice subjected to global cerebral ischemia suffered less neuronal injury (P<0.01, P<0.001) compared to wild-type littermates or placebo treated controls. There were also fewer microglia surrounding areas of injury, and less activation of the pro-inflammatory transcription factor, nuclear factor Kappa B (NFkB).<br />Interpretation: P2Y12 participates in ischemia related inflammation by mediating microglial migration and potentiation of neurotoxicity. These data also suggest an additional anti-inflammatory, neuroprotective benefit of clopidogrel.
- Subjects :
- Animals
Apoptosis
Astrocytes physiology
Brain Ischemia immunology
Brain Ischemia pathology
CA1 Region, Hippocampal immunology
CA1 Region, Hippocampal pathology
Cell Hypoxia
Cell Movement
Cell Survival
Cells, Cultured
Clopidogrel
Coculture Techniques
Gene Knockdown Techniques
Glucose deficiency
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
NF-kappa B metabolism
Neurons physiology
Purinergic P2Y Receptor Antagonists pharmacology
Receptors, Purinergic P2Y12 genetics
Ticlopidine analogs & derivatives
Ticlopidine pharmacology
Brain Ischemia metabolism
Microglia physiology
Receptors, Purinergic P2Y12 deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23940669
- Full Text :
- https://doi.org/10.1371/journal.pone.0070927