Selective block of adenosine A(2A) receptors prevents ischaemic‐like effects induced by oxygen and glucose deprivation in rat medium spiny neurons

BACKGROUND AND PURPOSE: 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: A(1), A(2A), A(2B) and A(3). Striatal medium spiny neurons (MSNs) express high levels of A(2A) receptors and are particularly vulnerable to ischaemic insults. A(2A) Receptor blockade reduces acute striatal post‐ischaemic damage but the cellular mechanisms involved are still unknown. EXPERIMENTAL APPROACH: We performed patch‐clamp recordings of MSNs in rat striatal slices subjected to oxygen and glucose deprivation (OGD) to investigate the effects of A(2A) receptor ligands or ion channel blockers on AD and OGD‐induced ionic imbalance, measured as a positive shift in E(rev) of ramp currents. KEY RESULTS: Our data indicate that the A(2A) receptor antagonist SCH58261 (10 μM) significantly attenuated ionic imbalance and AD appearance in MSNs exposed to OGD. The K(+) channel blocker Ba(2+) (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 A(2A) 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 Ba(2+), indicating facilitated glutamate release. CONCLUSION AND IMPLICATIONS: Adenosine, released during striatal OGD, activates A(2A) receptors that may exacerbate OGD‐induced damage through K(+) channel inhibition. Our results could help to develop A(2A) receptor‐selective therapeutic tools for the treatment of brain ischaemia.