Erythropoietin (EPO) prevents neuronal apoptosis after cerebral ischemia and metabolic stress. This study demonstrates that EPO protects neurons by inhibiting apoptosis, which is a key mechanism for its neuroprotective effects. Systemic administration of EPO after middle-cerebral artery occlusion in rats significantly reduces infarct volume and neuronal apoptosis in the ischemic penumbra. In vitro, EPO inhibits apoptosis induced by serum deprivation or kainic acid in both pure and mixed neuronal cultures. EPO's protective effect requires pretreatment and is sustained for 3 days without continued EPO presence. EPO also protects hippocampal neurons against hypoxia-induced death by activating extracellular signal-regulated kinases and Akt-1/protein kinase B. EPO is trophic but not mitogenic in cultured neuronal cells, suggesting it promotes survival rather than proliferation. These findings indicate that EPO's neuroprotective effects are primarily due to its antiapoptotic actions. Additionally, EPO may have longer-latency neurotrophic effects. The study supports the use of EPO as a neuroprotective therapy in acute brain injury, given its clinical safety. EPO is a hematopoietic growth factor but also has neurotrophic effects, expanding its biological role beyond hematopoiesis. EPO gene expression in the brain is regulated by hypoxia-inducible factor-1, which is activated by various stressors, including hypoxia. EPO protects cultured neurons against glutamate toxicity and reduces ischemic neuronal damage in rodent stroke models. The study also shows that EPO activates signaling pathways such as MAPK and PI(3)K, which are crucial for its neuroprotective effects. These pathways are involved in the antiapoptotic effects of BDNF in cortical neurons. The findings suggest that EPO's neuroprotective effects are mediated through the activation of specific protein kinases to promote cell survival. The study highlights the potential of EPO as a therapeutic agent for cerebral ischemia and other brain injuries.Erythropoietin (EPO) prevents neuronal apoptosis after cerebral ischemia and metabolic stress. This study demonstrates that EPO protects neurons by inhibiting apoptosis, which is a key mechanism for its neuroprotective effects. Systemic administration of EPO after middle-cerebral artery occlusion in rats significantly reduces infarct volume and neuronal apoptosis in the ischemic penumbra. In vitro, EPO inhibits apoptosis induced by serum deprivation or kainic acid in both pure and mixed neuronal cultures. EPO's protective effect requires pretreatment and is sustained for 3 days without continued EPO presence. EPO also protects hippocampal neurons against hypoxia-induced death by activating extracellular signal-regulated kinases and Akt-1/protein kinase B. EPO is trophic but not mitogenic in cultured neuronal cells, suggesting it promotes survival rather than proliferation. These findings indicate that EPO's neuroprotective effects are primarily due to its antiapoptotic actions. Additionally, EPO may have longer-latency neurotrophic effects. The study supports the use of EPO as a neuroprotective therapy in acute brain injury, given its clinical safety. EPO is a hematopoietic growth factor but also has neurotrophic effects, expanding its biological role beyond hematopoiesis. EPO gene expression in the brain is regulated by hypoxia-inducible factor-1, which is activated by various stressors, including hypoxia. EPO protects cultured neurons against glutamate toxicity and reduces ischemic neuronal damage in rodent stroke models. The study also shows that EPO activates signaling pathways such as MAPK and PI(3)K, which are crucial for its neuroprotective effects. These pathways are involved in the antiapoptotic effects of BDNF in cortical neurons. The findings suggest that EPO's neuroprotective effects are mediated through the activation of specific protein kinases to promote cell survival. The study highlights the potential of EPO as a therapeutic agent for cerebral ischemia and other brain injuries.