Purinergic Signalling (2007) 3:299–310 ces, adenosine stabilises the neuronal membrane potentials, thus reducing neuronal excitability [96]. Consequent reduc- tions in cellular metabolism and energy consumption [97] and moderate lowering of the body/brain temperature [98] are protective in ischemia. A1 receptor agonists are shown to attenuate ischemic or excitotoxic neuronal damage in both in vitro and in vivo models of cerebral ischemia (for review, see [99, 100]). In accordance, adenosine A1 antagonists given acutely exac- erbate the damage induced by ischemia in different animal models of ischemia. An unselective A1 receptor antagonist, theophylline, increased mortality [101, 102]. Unlike acute treatment, chronic administration of A1 agonists worsened survival and increased neuronal loss [103], a phenomenon thought to depend on A1 receptor desensitization. Although data converge in demonstrating a neuroprotec- tive effect of adenosine through A1 receptors during ischemia, the use of selective A1 agonists is hampered by unwanted peripheral effects, e.g. sedation, bradycardia, hypotension [104]. Von Lubitz and co-workers [105] have reported that post-ischemic administration of the A1 receptor agonist adenosine amine congener (ADAC), which induces fewer undesirable effects, increases survival in gerbils. Moreover, we may consider that administration of agents that elevate the local concentration of adenosine at the injury site, by inhibiting its metabolism to inosine or rephosphorylation to AMP or reuptake, may have the advantage of restricting the effect of such inhibitors to areas of injury-induced adenosine release [106]. More recently, the role of A2A receptors in ischemic neuroprotection has been studied. Gao and Phillis [107] demonstrated for the first time that the non-selective A2A receptor antagonist CGS 15943 reduces cerebral ischemic injury in the gerbil following global forebrain ischemia. Subsequently, many reports have confirmed the neuropro- tective role of A2A receptor antagonists in different models of ischemia. The selective A2A receptor antagonist SCH 58261 reduced ischemic brain damage in neonatal [108] and adult [83, 109] rat models of focal cerebral ischaemia. The same antagonist, subchronically administered, was protective against both brain damage and neurological deficit in the adult rat model of focal cerebral ischemia [110, 111]. Studies in A2A receptor knockout mice supported the neuroprotective role of A2A receptor antagonists on ischemic brain damage [112]. The beneficial effects of A2A antagonists in stroke were mainly attributed to reduced glutamate outflow [83, 110, 113]. Prolonged application of the A2A selective agonist CGS 21680 significantly reduced synaptic depression brought about by OGD in the hippocampus [59] and the same agonist promotes glutamate release under normoxic and ischemic conditions [70, 71, 114, 115]. In addition to neurones, adenosine A2A receptors are located on microglia [116, 117] and astrocytes [118]. On glial cells, A2A receptors 305 mediate inhibition of the glutamate uptake transporter, GLT- 1, and stimulate glutamate outflow [119]. A2A antagonists prevent the increase in glutamate levels induced by glutamate uptake inhibitors [120]. Therefore, the protective effects of A2A antagonists in brain ischemia may be largely due to reduced glutamate outflow from neurones and glial cells. Further support of a major role for glia in the neuro- protective effect of A2A antagonism in ischemia comes from the observation that subchronic administration of the A2A receptor antagonist SCH 58261 reduces p38 mitogen- activated protein kinase (MAPK) activation in striatal and cortical microglia 24 h after permanent focal ischemia [111]. Evidence indicates that p38 MAPK is activated in glia up to 24 h after ischemia [121, 122] and is involved, through transcriptional mechanisms, in neuronal death [123, 124]. Since SCH 58261 reduces glutamate outflow in the first hours after ischemia [83], reduced p38 MAPK activation may be due to a direct effect on glial A2A receptors or may be secondary to a reduction in the excitotoxic cascade that primes p38 activation [125]. The importance of A2A receptors under ischemia is highlighted by the observation that A2A receptor expression increases on neurones and microglia after ischemia [126]. Selective inactivation of A2A receptors on bone-marrow-derived cells (wild-type mice transplanted with A2A receptor knockout bone marrow cells) attenuates infarct volumes and ischemia-induced expression of several proinflammatory cytokines in the brain [127]. Therefore, protective effects of A2A antagonists may be attributed to inhibition of inflammation product production. In several studies, A2A receptor agonists have been found to be protective in the global ischemia model in the gerbil [128, 129]. Jones and co-workers [130] show that peripheral administration of the A2A receptor agonist CGS 21680 protects the hippocampus against kainate-induced excitotox- icity. However, the direct injection of CGS 21680 into the hippocampus failed to afford protection, while the A2A anta- gonist ZM 241385, when injected directly into the hippo- campus, reduced kainate-induced neuronal damage [131]. These data suggest that the neuroprotective properties of A2A agonists are mainly due to peripherally mediated effects. Major mechanisms that may account for A2A-mediated protection include inhibition of platelet aggregation and vasodilation [89] and anti-inflammatory actions. A2A recep- tors on neutrophils may account for inhibition of adhesion to endothelial cells and ensuing production of free radicals [132, 133]. On this basis, adenosine and its receptors are considered targets for therapeutic implementation in the treatment of stroke. At the moment, a possible adenosynergic therapeutic strategy after ischaemia that is worth consideration is that of increasing adenosine concentrations at the ischemic sites by inhibitors of adenosine metabolism or reuptake in association with adenosine A2A antagonists. When considering the