Selective block of adenosine A2A receptors prevents ischaemic-like effects induced by oxygen and glucose deprivation in rat medium spiny neurons.

<bold>Background and Purpose: </bold>Ischaemia is known to cause massive neuronal depolarization, termed anoxic depolarization (AD), due to energy failure and loss of membrane ion gradients. The neuromodulator adenosine accumulates extracellularly during ischaemia and activates four metabotropic receptors: A1 , A2A , A2B and A3 . Striatal medium spiny neurons (MSNs) express high levels of A2A receptors and are particularly vulnerable to ischaemic insults. A2A Receptor blockade reduces acute striatal post-ischaemic damage but the cellular mechanisms involved are still unknown.<bold>Experimental Approach: </bold>We performed patch-clamp recordings of MSNs in rat striatal slices subjected to oxygen and glucose deprivation (OGD) to investigate the effects of A2A receptor ligands or ion channel blockers on AD and OGD-induced ionic imbalance, measured as a positive shift in Erev of ramp currents.<bold>Key Results: </bold>Our data indicate that the A2A receptor antagonist SCH58261 (10 μM) significantly attenuated ionic imbalance and AD appearance in MSNs exposed to OGD. The K+ channel blocker Ba2+ (2 mM) or the Na+ channel blocker tetrodotoxin (1 μM) exacerbated and attenuated, respectively, OGD-induced changes. Spontaneous excitatory post-synaptic current (sEPSC) analysis in MSNs revealed that the A2A receptor agonist CGS21680 (1 μM) prevented OGD-induced decrease of sEPSCs within the first 5 min of the insult, an effect shared by the K+ channel blocker Ba2+ , indicating facilitated glutamate release.<bold>Conclusion and Implications: </bold>Adenosine, released during striatal OGD, activates A2A receptors that may exacerbate OGD-induced damage through K+ channel inhibition. Our results could help to develop A2A receptor-selective therapeutic tools for the treatment of brain ischaemia. [ABSTRACT FROM AUTHOR]