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Glutamate extracellular accumulation is an early event in brain ischemia triggering excitotoxic neuron damage. We have investigated how to control the glutamate efflux from human cerebrocortical slices superfused in conditions simulating an acute ischemic insult (oxygen and glucose deprivation). The efflux of previously accumulated [3H]D-aspartate or endogenous glutamate increased starting 18 min after exposure to ischemia and returned almost to basal values in 6 min reperfusion with standard medium. Superfusion with Ca2+-free, EGTA (0.5 mM)-containing medium or with medium containing tetrodotoxin (TTX; 0.5 μM) inhibited the ischemia (24 min)-evoked [3H]D-aspartate efflux by about 50% and 65%, respectively. The ischemia (24 or 36 min)-evoked efflux of [3H]D-aspartate or endogenous glutamate was reduced at least 40% by the adenosine A2A receptor antagonist SCH 58261 (1 μM); the compound was effective when added up to 15 min after exposure to ischemia. No effect of SCH 58261 on the ischemia-evoked [3H]D-aspartate was found in Ca2+-free, EGTA-containing medium. To conclude, a significant component of the ischemia-evoked glutamate efflux in human cerebrocortical slices seems to occur by a vesicular-like mechanism. Endogenously released adenosine is likely to activate A2A receptors that enhance vesicular-like glutamate release during ischemia; A2A receptor antagonists would deserve consideration for their neuroprotective potential. [Copyright &y& Elsevier]

Adenosine released during cerebral ischemia is considered to act as a neuroprotectant, possibly through the inhibition of glutamate release. The involvement of A1 and A2A receptors in the control of the rise of extracellular glutamate during ischemia was investigated by monitoring the effects of selective A1 and A2A receptor antagonists on ischemia-evoked glutamate release in rat cerebrocortical slices.Slices were superfused with oxygen- and glucose-deprived medium and [3H]d-aspartate or endogenous glutamate was measured in the superfusate fractions. Withdrawal of Ca2+ ions or addition of tetrodotoxin more than halved the ischemia-evoked efflux of [3H]d-aspartate or glutamate, compatible with a vesicular-like release. The glutamate transporter inhibitor dl-TBOA prevented the ischemia-evoked efflux of [3H]d-aspartate by about 40%, indicating a carrier-mediated efflux. The ischemia-evoked efflux of [3H]d-aspartate or glutamate was increased by the A1 receptor antagonist DPCPX. The A2A antagonist SCH 58261 decreased [3H]d-aspartate or endogenous glutamate efflux (50 and 55% maximal inhibitions; EC50: 14.9 and 7.6 nM, respectively); the drug was effective also if added during ischemia. No effect of either the A1 or the A2A receptor antagonist was found on the ischemia-evoked efflux of [3H]d-aspartate in Ca2+-free medium. Our data suggest that adenosine released during cerebral ischemia can activate inhibitory A1 and stimulatory A2A receptors that down- or up-regulate the vesicular-like component of glutamate release. [Copyright &y& Elsevier]