A₃ receptors in cortical neurons: Pharmacological aspects and neuroprotection during hypoxia

Adenosine, which is released under pathophysiological conditions such as hypoxia or ischemia, is involved in a variety of regulatory processes related to neuroprotection. Major advances in the research on neuronal adenosine receptors have provided a better understanding of the mechanisms underlying the neuroprotective effects during hypoxia. The therapeutic potential of adenosine was recognized several years ago, but only the development of stable and selective adenosine receptor agonists and antagonists has offered novel approaches for the pharmacological manipulation of the receptor activity. To date, four G protein coupled receptors have been cloned and identified in the central nervous system: A 1 , A 2A , A 2B , and A 3. The neuroprotective effects of adenosine are mediated primarily by the activation of A 1 receptors. Knowledge of the physiological role of A 3 receptors in the brain is still limited. This article focuses on new evidences referring to possible functions of A 3 receptors in the CNS, especially the role during hypoxia. Electrophysiological investigations on brain slices give us new insights concerning mechanisms of synaptic modulation. The data from pyramidal cells of the rat cingulate cortex show that a high level of endogenous adenosine (occuring during hypoxia) activates A 3 receptors, which mediates a depression of the synaptic transmission. The A 3 receptors inhibit the glutamate release additionally to and independently from the A 1 receptors. The two distinct mechanisms of synaptic modulation contribute to the neuroprotective action of adenosine during hypoxia and offer new approaches for therapeutic strategies. Drug Dev. Res. 58:420–427, 2003.