Mutant Erythropoietin Without Erythropoietic Activity Is Neuroprotective Against Ischemic Brain Injury

Background and Purpose—Erythropoietin (EPO) confers potent neuroprotection against ischemic injury. However, treatment for stroke requires high doses and multiple administrations of EPO, which may cause deleterious side effects due to its erythropoietic activity. This study identifies a novel nonerythropoietic mutant EPO and investigates its potential neuroprotective effects and underlying mechanism in an animal model of cerebral ischemia. Methods—We constructed a series of mutant EPOs, each containing a single amino acid mutation within the erythropoietic motif, and tested their erythropoietic activity. Using cortical neuronal cultures exposed to N-methyl-d-aspartate neurotoxicity and a murine model of transient middle cerebral artery occlusion, neuroprotection and neurofunctional outcomes were assessed as well as activation of intracellular signaling pathways. Results—The serine to isoleucine mutation at position 104 (S104I-EPO) completely abolished the erythropoietic and platelet-stimulating activity o...