Modulation of glutamate release and excitotoxicity by adenosine A2A receptors

Because an increased glutamate outflow is thought to play a crucial role in triggering excitotoxic neuronal death, drugs able to regulate glutamate release could be effective for the management of neurodegenerative diseases. In this article, the authors discuss the hypothesis that adenosine A 2A receptor antagonists (A 2A antagonists) may belong to the aforementioned category. In rats bilaterally lesioned with the excitotoxin quinolinic acid (QA) in the striatum, the A 2A antagonist SCH 58261 significantly reduced the motor, EEG, and neuropathologic changes induced by the lesion. Such effects of SCH 58261 occurred only at low doses and were paralleled by an inhibition of QA-stimulated glutamate release. The role played by A 2A antagonists in the regulation of glutamate outflow was also confirmed by preliminary results obtained in the model of paired-pulse stimulation in corticostriatal slices. Conversely, based on data obtained in cultured striatal neurons, A 2A antagonists appear unable to directly inhibit NMDA effects. In conclusion, A 2A antagonists show clear neuroprotective effects in models of brain injury, although their actual therapeutic potential needs to be confirmed in a wider range of doses and in models of neurodegenerative diseases in which presynaptic and postsynaptic effects play different relative roles.