Adenosine and cerebral ischemia: therapeutic future or death of a brave concept?

Numerous studies have consistently shown that agonist stimulation of adenosine A1 receptors results in a significant reduction of morbidity and mortality associated with global and focal brain ischemia in animals. Based on these observations, several authors have suggested utilization of adenosine A1 receptors as targets for the development of clinically viable drugs against ischemic brain disorders. Recent advent of adenosine A1 receptor agonists characterized by lowered cardiovascular effects added additional strength to this argument. On the other hand, although cardioprotective, adenosine A3 receptor agonists proved severely cerebrodestructive when administered prior to global ischemia in gerbils. Moreover, stimulation of adenosine A3 receptors appears to reduce the efficacy of some of the neuroprotective actions mediated by adenosine A1 receptors. The review discusses the possible role of adenosine receptor subtypes (A1, A2, and A3) in the context of their involvement in the pathology of cerebral ischemia, and analyzes putative strategies for the development of clinically useful strategies based on adenosine and its receptors. It also stresses the need for further experimental studies before definitive conclusions on the usefulness of the adenosine concept in the treatment of brain ischemia can be made.