This study provides in vivo evidence that erythropoietin (EPO), a glycoprotein produced by the kidney and liver, protects neurons from ischemic damage. EPO stimulates erythropoiesis and has been shown to protect primary cultured neurons from NMDA receptor-mediated glutamate toxicity. The researchers infused EPO into the lateral ventricles of gerbils, preventing ischemia-induced learning disability and rescuing hippocampal CA1 neurons from lethal ischemic damage. The neuroprotective effect was confirmed by counting synapses in the hippocampal CA1 region. Infusion of soluble EPOR (an extracellular domain capable of binding with the ligand) into animals given mild ischemic treatment caused neuronal degeneration and impaired learning ability, whereas infusion of heat-denatured soluble EPOR was not detrimental. This suggests that endogenous brain EPO is crucial for neuronal survival. In vitro experiments further showed that EPO may exert its neuroprotective effect by reducing NO-mediated free radical formation or antagonizing their toxicity. The study highlights the importance of EPO in maintaining neuronal viability during and after nonlethal brain ischemia.This study provides in vivo evidence that erythropoietin (EPO), a glycoprotein produced by the kidney and liver, protects neurons from ischemic damage. EPO stimulates erythropoiesis and has been shown to protect primary cultured neurons from NMDA receptor-mediated glutamate toxicity. The researchers infused EPO into the lateral ventricles of gerbils, preventing ischemia-induced learning disability and rescuing hippocampal CA1 neurons from lethal ischemic damage. The neuroprotective effect was confirmed by counting synapses in the hippocampal CA1 region. Infusion of soluble EPOR (an extracellular domain capable of binding with the ligand) into animals given mild ischemic treatment caused neuronal degeneration and impaired learning ability, whereas infusion of heat-denatured soluble EPOR was not detrimental. This suggests that endogenous brain EPO is crucial for neuronal survival. In vitro experiments further showed that EPO may exert its neuroprotective effect by reducing NO-mediated free radical formation or antagonizing their toxicity. The study highlights the importance of EPO in maintaining neuronal viability during and after nonlethal brain ischemia.