title: Epobis is a Nonerythropoietic and Neuroprotective Agonist of the Erythropoietin Receptor with Anti-Inflammatory and Memory Enhancing Effects.
abstract: The cytokine erythropoietin (EPO) stimulates proliferation and differentiation of erythroid progenitor cells. Moreover, EPO has neuroprotective, anti-inflammatory, and antioxidative effects, but the use of EPO as a neuroprotective agent is hampered by its erythropoietic activity. We have recently designed the synthetic, dendrimeric peptide, Epobis, derived from the sequence of human EPO. This peptide binds the EPO receptor and promotes neuritogenesis and neuronal cell survival. Here we demonstrate that Epobisin vitropromotes neuritogenesis in primary motoneurons and has anti-inflammatory effects as demonstrated by its ability to decrease TNF release from activated AMJ2-C8 macrophages and rat primary microglia. When administered systemically Epobis is detectable in both plasma and cerebrospinal fluid, demonstrating that the peptide crosses the blood-brain barrier. Importantly, Epobis is not erythropoietic, but systemic administration of Epobis in rats delays the clinical signs of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, and the peptide has long-term, but not short-term, effects on working memory, detected as an improved social memory 3 days after administration. These data reveal Epobis to be a nonerythropoietic and neuroprotective EPO receptor agonist with anti-inflammatory and memory enhancing properties.
authors.affiliation: Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Oksana
authors.identifier: 0000-0002-2075-338X
authors.initials: O
authors.lastname: Dmytriyeva
authors.affiliation: Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Juliane Marie Centret, Rigshospitalet (Copenhagen University Hospital), Copenhagen, Denmark.
authors.forename: Stanislava
authors.identifier: 0000-0002-5406-5163
authors.initials: S
authors.lastname: Pankratova
authors.affiliation: Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Irina
authors.initials: I
authors.lastname: Korshunova
authors.affiliation: Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter S
authors.identifier: 0000-0001-6350-2727
authors.initials: PS
authors.lastname: Walmod
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy; D004921:Erythropoietin / Q000737:chemistry; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016501:Neurites / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000893:Anti-Inflammatory Agents; C554270:EPO protein, human; D018696:Neuroprotective Agents; D010455:Peptides; D004921:Erythropoietin