Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress

Erythropoietin (EPO) promotes neuronal survival after hypoxia and other met abolic insults by largely unknown mechanisms. Apoptosis and necrosis have b een proposed as mechanisms of cellular demise, and either could be the targ et of actions of EPO. This study evaluates whether antiapoptotic mechanisms can account for the neuroprotective actions of EPO, Systemic administratio n of EPO (5,000 units/kg of body weight, i.p.) after middle-cerebral artery occlusion in rats dramatically reduces the volume of infarction 24 h later , in concert with an almost complete reduction in the number of terminal de oxynucleotidyltransferase-mediated dUTP nick-end labeling of neurons within the ischemic penumbra. In both pure and mixed neuronal cultures, EPO (0.1- 10 units/ml) also inhibits apoptosis induced by serum deprivation or kainic acid exposure. Protection requires pretreatment, consistent with the induc tion of a gene expression program, and is sustained for 3 days without the continued presence of EPO, EPO (0.3 units/ml) also protects hippocampal neu rons against hypoxia-induced neuronal death through activation of extracell ular signal-regulated kinases and protein kinase Akt-1/protein kinase B, Th e action of EPO is not limited to directly promoting cell survival, as EPO is trophic but not mitogenic in cultured neuronal cells. These data suggest that inhibition of neuronal apoptosis underlies short latency protective e ffects of EPO after cerebral ischemia and other brain injuries. The neurotr ophic actions suggest there may be longer-latency effects as well. Evaluati on of EPO, a compound established as clinically safe, as neuroprotective th erapy in acute brain injury is further supported.