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.

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

“…Similar observations were made by von Lubitz in a similar gerbil model of brain ischemia [227]. However, this concept of A 2A R blockade as a neuroprotective strategy was difficult to understand at the time and consequently was not widely accepted until the group of Ongini and the group of Chen demonstrated that both the pharmacological blockade of A 2A Rs with a selective antagonist (SCH 582610) [228] as well as the genetic inactivation of A 2A Rs (using A 2A R knockout mice) [229] conferred a robust neuroprotection in animal models of focal ischemia.…”

“…Interestingly, this neuroprotection afforded by A 2A R blockade was more robust in cortical regions than in the basal ganglia, where these A 2A Rs are considerably more abundant [228,229,231]. This emphasises again that the Fabnormal_ high density of A 2A Rs in striatal medium spiny neurons of the indirect pathway fulfils a very particular role in the control of striatal circuitry and that our knowledge about striatal A 2A Rs should not be extrapolate to understand the general role of A 2A Rs in the brain.…”

“…This emphasises again that the Fabnormal_ high density of A 2A Rs in striatal medium spiny neurons of the indirect pathway fulfils a very particular role in the control of striatal circuitry and that our knowledge about striatal A 2A Rs should not be extrapolate to understand the general role of A 2A Rs in the brain. Nevertheless, although A 2A R blockade is particularly effective in preventing cortical and hippocampal damage [225, 229, 231Y237], it is also effective in attenuating striatal damage following brain ischemia [229,231], exposure to quinolinic acid [230,238], 3-nitropropionic acid [239,240], malonate [241] or MPTP [242,243].…”

Adenosine Signaling in Striatal Circuits and Alcohol Use Disorders

“…Furthermore, mice lacking A2AR (Chen et al, 1999;Ledent et al, 1997) have been shown to demonstrate reduced sensitivity to the hypnotic effects of alcohol, increased alcohol consumption, and reduced alcohol-withdrawal seizures (El Yacoubi et al, 2001;Naassila et al, 2002). As a result, antagonism of A2AR signaling could be useful in the treatment of alcohol withdrawal symptoms; however, since inhibition of A2AR also results in increased alcohol consumption, the mechanisms through which the A2AR mediates each of these effects should be further delineated to identify a more specific therapeutic approach.…”

Striatal Adenosine A2A and Cannabinoid CB1 Receptors Form Functional Heteromeric Complexes that Mediate the Motor Effects of Cannabinoids

“…The rat was the target animal species, as it was the most suitable to study the behavioral effects of intrastriatal administration of cannabinoid agonists. A 2A receptor KO and CB 1 receptor KO mice were generated as described elsewhere (Ledent et al, 1999;Chen et al, 1999). All animals used in a given experiment originated from the same breeding series, and were matched for age and weight.…”