Aspirin reduces the size of infarcts after ischaemic stroke. Although this fact has been attributed to its antiplatelet actions, direct neuroprotective effects have been also reported. We have demonstrated that aspirin is neuroprotective by inhibiting glutamate release in "in vitro" models of brain ischaemia. A pharmacological dissection of the components involved, using cell cortical culture exposed to oxygen-glucose deprivation, indicated that aspirin selectively inhibits the increase in extracellular glutamate concentration which results from reversal of the glutamate transporter, a component of release which is due to ATP depletion. Moreover, the neuroprotection afforded by aspirin occurred in parallel to a lesser decay in ATP levels after OGD. Aspirin not only elevated ATP levels in intact cortical neurones, but also in isolated brain mitochondria. On the other hand, using a whole-animal model of permanent focal brain ischaemia (MCAO; middle cerebral artery occlusion), wed have also demonstrated that aspirin (30 mg/Kg i.p. administered 2 h before the occlusion) produced a significant reduction in infarct volume, effect that correlated with the inhibition caused by aspirin on ischaemia-induced increase in brain and serum glutamate concentrations after the onset of the ischaemia. Aspirin also inhibited ischaemia-induced decrease in brain ATP levels. Finally, clinical studies showed that prior treatment with aspirin was associated with a lower risk of neurological deterioration after acute ischemic stroke which was related to a reduction of glutamate release. Our present findings show a novel mechanism for the neuroprotective effects of aspirin, that takes place at concentrations in the antiaggregant-analgesic range, useful in the management of patients with risk of ischaemic events.