Decreased neuronal survival-signaling and brain damage: Stroke is a leading cause of death worldwide, the major cause of adult disability and second of dementia. In spite of the social and economic importance of this disorder, and after intense research, no effective drugs have yet reached the clinic. Blood reperfusion with the thrombolytic agent tissue plasminogen activator remains the only pharmacologic treatment currently available for ischemic stroke, the major type of brain infarction (> 85％ of total cases). Damage in this situation results from thrombotic or embolic occlusion of a cerebral artery causing a decrease of blood flow to a specific area of the brain parenchyma, neurons being particularly sensitive to a reduction of the supply of glucose and oxygen. It is thus a priority to develop neuroprotective strategies able to preserve neurons from the ischemic injury and, in this way, reduce brain damage and patient disability. A promising approach involves rescue of the area of penumbra surrounding the infarct, a region functionally silent but structurally intact. However, neurons in the penumbra can undergo a process of delayed death known as excitotoxicity, caused by overstimulation of the N-methyl-D-aspartate type of excitatory glutamate receptors (NMDARs). The critical role played by these receptors in synaptic plasticity, learning and memory, together with dual functions in neuronal survival and death (Hardingham et al., 2002), underlies previous failure of NMDAR blockade as a therapeutic target in stroke.