This study investigates the neuroprotective effects of erythropoietin (EPO) in preventing neuronal apoptosis after cerebral ischemia and metabolic stress. EPO, initially characterized as a hematopoietic growth factor, has been found to be expressed in brain tissue and to have neuroprotective properties. The research evaluates whether EPO's neuroprotective actions are mediated through antiapoptotic mechanisms. Key findings include: 1. **In Vivo Studies**: Systemic administration of EPO (5,000 units/kg) after middle-cerebral artery occlusion in rats significantly reduces infarct volume and the number of apoptotic neurons within the ischemic penumbra 24 hours later. 2. **In Vitro Studies**: EPO (0.1–10 units/ml) inhibits apoptosis in pure and mixed neuronal cultures induced by serum deprivation or kainic acid exposure. This protection is dependent on pretreatment with EPO and is sustained for up to 3 days without continuous EPO administration. 3. **Mechanistic Studies**: EPO protects hippocampal neurons against hypoxia-induced death by activating extracellular signal-regulated kinases (ERKs) and protein kinase Akt-1/protein kinase B (PI(3)K/Akt). The neuroprotective effect is not due to mitogenic activity but rather to trophic effects. 4. **Signaling Pathways**: EPO activates ERKs and PI(3)K, which are crucial for its neuroprotective action. Specific inhibitors of these pathways largely abrogate the neuroprotective effects of EPO. 5. **Clinical Relevance**: The neurotrophic actions of EPO suggest potential longer-latency effects and support the evaluation of EPO as a neuroprotective therapy in acute brain injuries. The study concludes that EPO's neuroprotective actions are primarily mediated through inhibition of neuronal apoptosis via activation of specific protein kinases, and that its trophic effects further enhance its therapeutic potential.This study investigates the neuroprotective effects of erythropoietin (EPO) in preventing neuronal apoptosis after cerebral ischemia and metabolic stress. EPO, initially characterized as a hematopoietic growth factor, has been found to be expressed in brain tissue and to have neuroprotective properties. The research evaluates whether EPO's neuroprotective actions are mediated through antiapoptotic mechanisms. Key findings include: 1. **In Vivo Studies**: Systemic administration of EPO (5,000 units/kg) after middle-cerebral artery occlusion in rats significantly reduces infarct volume and the number of apoptotic neurons within the ischemic penumbra 24 hours later. 2. **In Vitro Studies**: EPO (0.1–10 units/ml) inhibits apoptosis in pure and mixed neuronal cultures induced by serum deprivation or kainic acid exposure. This protection is dependent on pretreatment with EPO and is sustained for up to 3 days without continuous EPO administration. 3. **Mechanistic Studies**: EPO protects hippocampal neurons against hypoxia-induced death by activating extracellular signal-regulated kinases (ERKs) and protein kinase Akt-1/protein kinase B (PI(3)K/Akt). The neuroprotective effect is not due to mitogenic activity but rather to trophic effects. 4. **Signaling Pathways**: EPO activates ERKs and PI(3)K, which are crucial for its neuroprotective action. Specific inhibitors of these pathways largely abrogate the neuroprotective effects of EPO. 5. **Clinical Relevance**: The neurotrophic actions of EPO suggest potential longer-latency effects and support the evaluation of EPO as a neuroprotective therapy in acute brain injuries. The study concludes that EPO's neuroprotective actions are primarily mediated through inhibition of neuronal apoptosis via activation of specific protein kinases, and that its trophic effects further enhance its therapeutic potential.