Erythropoietin (EPO), a hormone produced by the kidney and liver, is known to stimulate red blood cell production. However, recent studies suggest that EPO also plays a neuroprotective role in the central nervous system. This study provides in vivo evidence that EPO protects neurons from ischemic damage. In gerbils, EPO infusion into the lateral ventricles prevented ischemia-induced learning disability and rescued hippocampal CA1 neurons from lethal damage. The neuroprotective effect of EPO was confirmed by increased synapse numbers in the hippocampal CA1 region. Additionally, soluble EPO receptor (sEPOR) infusion under mild ischemia caused neuronal degeneration and impaired learning, while heat-denatured sEPOR did not. These findings suggest that endogenous brain EPO is crucial for neuronal survival. EPO did not repress NMDA receptor-mediated Ca²+ influx but rescued neurons from NO-induced death, indicating that EPO may protect neurons by reducing NO-mediated free radical formation or antagonizing their toxicity. The study also shows that EPO protects cultured neurons from glutamate toxicity, and that EPO does not block NMDA receptor-mediated Ca²+ influx, suggesting that EPO's neuroprotective effect is related to suppressing NO toxicity rather than Ca²+ increase. The results indicate that EPO plays a critical role in protecting neurons from ischemic damage, and that its neuroprotective action is mediated through mechanisms involving NO and free radicals. The study highlights the importance of EPO in neuronal survival and recovery after ischemic injury.Erythropoietin (EPO), a hormone produced by the kidney and liver, is known to stimulate red blood cell production. However, recent studies suggest that EPO also plays a neuroprotective role in the central nervous system. This study provides in vivo evidence that EPO protects neurons from ischemic damage. In gerbils, EPO infusion into the lateral ventricles prevented ischemia-induced learning disability and rescued hippocampal CA1 neurons from lethal damage. The neuroprotective effect of EPO was confirmed by increased synapse numbers in the hippocampal CA1 region. Additionally, soluble EPO receptor (sEPOR) infusion under mild ischemia caused neuronal degeneration and impaired learning, while heat-denatured sEPOR did not. These findings suggest that endogenous brain EPO is crucial for neuronal survival. EPO did not repress NMDA receptor-mediated Ca²+ influx but rescued neurons from NO-induced death, indicating that EPO may protect neurons by reducing NO-mediated free radical formation or antagonizing their toxicity. The study also shows that EPO protects cultured neurons from glutamate toxicity, and that EPO does not block NMDA receptor-mediated Ca²+ influx, suggesting that EPO's neuroprotective effect is related to suppressing NO toxicity rather than Ca²+ increase. The results indicate that EPO plays a critical role in protecting neurons from ischemic damage, and that its neuroprotective action is mediated through mechanisms involving NO and free radicals. The study highlights the importance of EPO in neuronal survival and recovery after ischemic injury.