Erythropoietin prevents neur cerebral ischemia and metab

Erythropoietin (EPO) promotes neuronal survival after hypoxia and hy other metabolic insults by largely unknown mechanisms. Apoptoro sis and necrosis have been proposed as mechanisms of cellular demise, and either could be the target of actions of EPO. This study wi evaluates whether antiapoptotic mechanisms can account for the ist neuroprotective actions of EPO. Systemic administration of EPO afi (5,000 units/kg of body weight, i.p.) after middle-cerebral artery ph occlusion in rats dramatically reduces the volume of infarction 24 h (Ji later, in concert with an almost complete reduction in the number do of terminal deoxynucleotidyltransferase-mediated dUTP nick-end ac labeling of neurons within the ischemic penumbra. In both pure [P and mixed neuronal cultures, EPO (0.1-10 units/ml) also inhibits an apoptosis induced by serum deprivation or kainic acid exposure. efi Protection requires pretreatment, consistent with the induction of pr a gene expression program, and is sustained for 3 days without the continued presence of EPO. EPO (0.3 units/ml) also protects hipne pocampal neurons against hypoxia-induced neuronal death grn on through activation of extracellular signal-regulated kinases and on protein kinase Akt-1/protein kinase B. The action of EPO is not I limited to directly promoting cell survival, as EPO is trophic but not b mitogenic in cultured neuronal cells. These data suggest that n inhibition of neuronal apoptosis underlies short latency protective effects of EPO after cerebral ischemia and other brain injuries. The a ce