Administration of EPO rescues the penumbra after cerebral ischemia. An ischemic core (IC; panel E) is caused by a 1-h occlusion of the middle cerebral artery distal to the rhinal artery in a rat, followed by reperfusion (stage 1 injury response, performed according to the methodology seen in references 8 and 81). TNFα and other proinflammatory cytokines are produced within this central volume of injury corresponding to the circulatory territory of the middle cerebral artery (MCA) and diffuse into the adjacent cerebral cortex to the right of IC (stage 2 injury response). Microglia (the macrophage equivalents of the nervous system) are recruited into the penumbra (right panels) and amplify injury. Within the penumbra, the TPR is subsequently upregulated (stage 3 injury response), but upregulation of its ligand EPO is suppressed. Therefore, EPO does not penetrate very far into the penumbra from the unsuppressed periphery, producing a large lesion when evaluated 24 h later (light gray area, panel S). However, parenteral administration of EPO (panel E) rescues the penumbra by delivering TPR ligand into this region primed for TPR activity but deficient in endogenous EPO.