Prolonged Beneficial Effect of Brief Erythropoietin Peptide JM4 Therapy on Chronic Relapsing EAE
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ORIGINAL ARTICLE
Prolonged Beneficial Effect of Brief Erythropoietin Peptide JM4 Therapy on Chronic Relapsing EAE Deeya Gaindh 1,2 & Yun-Beom Choi 1,2 & Michelle Marchese 1 & Peter Dowling 1,2 & Stuart Cook 1,2 & Benjamin Blumberg 1 & James H. Park 1 & Wei Lu 1 Accepted: 27 August 2020 # The Author(s) 2020
Abstract Potent beneficial immunomodulatory and anti-inflammatory effects of whole-molecule erythropoietin have been demonstrated in a variety of animal disease models including experimental autoimmune encephalomyelitis (EAE); however, excessive hematopoiesis limits its use in clinical applications. Our group previously generated an Epo-derived small peptide JM4 that is side-effect free and has strong neuroprotective activity without hematologic effects. Here, we investigated the long-term clinical effects of brief treatment with JM4 in chronic relapsing EAE using bioluminescence imaging (BLI) in transgenic mice containing the luciferase gene driven by the murine GFAP promoter. EAE mice treated with JM4 exhibited marked improvement in clinical scores and showed fewer disease flareups than control animals. JM4 therapy concomitantly led to markedly decreased GFAP bioluminescence in the brain and spinal cord in both acute and chronic relapsing EAE mouse models. We found a marker for toxic A1 astrocytes, complement component C3, that is upregulated in the brain and cord of EAE mice and sharply reduced in JM4-treated animals. In addition, an abnormally leaky neurovascular unit permeability was rapidly normalized within 5 days by JM4 therapy. The prolonged therapeutic benefit seen following brief JM4 treatment in EAE mice closely resemble that recently described in humans receiving pulsed immune reconstitution therapy with the disease-modifying compounds, alemtuzumab and cladribine. Our study suggests that JM4 therapy may have widespread clinical applicability for long-term treatment of inflammatory demyelinating diseases and that BLI is a useful noninvasive means of monitoring murine disease activity of the central nervous system. Keywords Erythropoietin (Epo) . JM4 peptide . Multiple sclerosis . Experimental autoimmune encephalomyelitis (EAE) . Bioluminescence imaging (BLI)
Introduction Experimental autoimmune encephalomyelitis (EAE) is a T cell–mediated autoimmune disease affecting the central Stuart Cook was previously affiliated to VA Medical Center of East Orange and Rutgers New Jersey Medical School but is currently retired. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13311-020-00923-5) contains supplementary material, which is available to authorized users. * Deeya Gaindh [email protected] 1
Neurology Service, VA Medical Center of East Orange, East Orange, NJ, USA
2
Department of Neurology, Rutgers New Jersey Medical School, Newark, NJ, USA
nervous system (CNS) in laboratory animals that leads to progressive weakness closely resembling the clinical manifestations of multiple sclerosis (MS) [1]. Due to the clinical and immunopathological similarities to
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