Microglial P2Y12 Deficiency/Inhibition Protects against Brain Ischemia

I'm sure your doctor can explain this(snort, snort).
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0070927

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.

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.

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).

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.