A_2AAdenosine Receptor Deficiency Attenuates Brain Injury Induced by Transient Focal Ischemia in Mice

Abstract

Extracellular adenosine critically modulates ischemic brain injury, at least in part through activation of the A 1 adenosine receptor. However, the role played by the A 2A receptor has been obscured by intrinsic limitations of A 2A adenosinergic agents. To overcome these pharmacological limitations, we explored the consequences of deleting the A 2A adenosine receptor on brain damage after transient focal ischemia. Cerebral morphology, as well as vascular and physiological measures (before, during, and after ischemia) did not differ between A 2A receptor knock-out and wild-type littermates. The volume of cerebral infarction, as well as the associated neurological deficit induced by transient filament occlusion of the middle cerebral artery, were significantly attenuated in A 2A receptor knock-out mice. This neuroprotective phenotype of A 2A receptor-deficient mice was observed in different genetic backgrounds, confirming A 2A receptor disruption as its cause. Together with complimentary pharmacological studies, these data suggest that A 2A receptors play a prominent role in the development of ischemic injury within brain and demonstrate the potential for anatomical and functional neuroprotection against stroke by A 2A receptor antagonists.