2. During cerebral ischemia, the N-methyl-D-aspartate (NMDA) receptor-mediated glutamate toxicity is the major cause of neuron death [Morishita 1997]. Glutamate toxicity is in part mediated by nitric oxide (NO). EPO up-regulates the expression of antioxidant enzymes on a transcriptional level in vascular smooth muscle cells [Kusano 1999], and can potentially protect neurons from NO-generating agents [Sakanaka 1998]. Furthermore, EPO can suppress the increase in Ca2+ concentration induced by glutamate and the nitric oxide (NO)-induced apoptosis [Morishita 1997].