Stimulation of Adenosine A3Receptors in Cerebral Ischemia: Neuronal Death, Recovery, or Both?

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Abstract
The role of the adenosine A3receptor continues to baffle, and, despite an increasing number of studies, the currently available data add to, rather than alleviate, the existing confusion. The reported effects of adenosine A3receptor stimulation appear to depend on the pattern of drug administration (acute vs. chronic), dose, and type of the target tissue. Thus, while acute exposure to A3receptor agonists protects against myocardial ischemia, it is severely damaging when these agents are given shortly prior to cerebral ischemia. Mast cells degranulate when their A3receptors are stimulated. Degranulation of neutrophils is, on the other hand, impaired. While reduced production of reactive nitrogen species has been reported following activation of A3receptors in collagen‐induced arthritis, the process appears to be enhanced in cerebral ischemia. Indeed, immunocytochemical studies indicate that both pre‐ and postischemic treatment with A3receptor antagonist dramatically reduces nitric oxide synthase in the affected hippocampus. Even more surprisingly, low doses of A3receptor agonists seem to enhance astrocyte proliferation, while high doses induce their apoptosis. This review concentrates on the studies of cerebral A3receptors and, based on the available evidence, discusses the possibility of adenosine A3receptor serving as an integral element of the endogenous cerebral neuroprotective complex consisting of adenosine and its receptors.