Adenosine and Stroke

The concentration of adenosine in the brain increases dramatically during ischemia, and adenosine has long been known to act predominantly as a neuroprotectant during ischemia. In agreement, adenosine infusion into the ischemic striatum significantly ameliorates neurological outcome and reduces the infarct volume after transient focal cerebral ischemia. Despite the neuroprotective effect of adenosine through A1 receptors during ischemia, the use of selective A1 agonists is hampered by unwanted peripheral effects such as sedation, bradycardia, and hypotension. An alternative therapeutic approach may consist of using agents that elevate the local concentration of adenosine at areas of injury-induced adenosine release, thus minimizing undesirable peripheral and central effects mediated by A1 receptors. Adenosine-potentiating agents at injury sites may act by (1) inhibiting its metabolism by adenosine kinase or adenosine deaminase, (2) preventing its transport through equilibrative membrane transporters (ENTs), (3) enhancing hydrolysis of extracellular ATP by use of nucleoside triphosphate diphosphohydrolases (NTPDases) and ecto-5′-nucleotidase (e5′-NTs). The role of A2A receptors also is important for neuroprotection during ischemia. Evidence suggests that low doses of A2A antagonists (that do not modify hemodynamic parameters) provide protection via centrally mediated control of precocious excessive excitotoxicity, while A2A agonists provide protection by controlling massive cell infiltration in the hours after ischemia. Information suggests that A2A receptors are a potentially attractive therapeutic target in ischemia. In perspective of using adenosine A2A active drugs to protect against brain ischemia, attention should be given to the dose and administration time after injury. Although much is still to be learned about the function of the A3 receptor, at the present time it can be speculated that A3 receptor selective ligands may be useful in the treatment of ischemic conditions involving inflammation.