First, we studied the neuroprotective effects of guanosine in an ex vivo model of brain ischemia, both in wild-type and A2AR deficient (A2AR−/−) mice; subsequently, we aimed to elucidate, in vitro, both the putative guanosine binding and activation of the A1R/A2AR heteromer. Here, ADORA2A is linked to brain ischemia.