Exploring Erythropoietin as a Neuroprotective and Neuroreparative Agent

Manuela Mengozzi

Student thesis: Doctoral Thesis

Abstract

Erythropoietin (EPO), a type 1 cytokine, is the main hormone regulating erythropoiesis; recombinant EPO is widely used to treat anaemia. In addition, EPO has been defined a tissue-protective cytokine for its extra-erythropoietic protective and reparative effects. In the last twenty years, extensive preclinical research and clinical studies have reported the neuroprotective effects of EPO in a variety of models of disease and injury of the nervous system; these include stroke, traumatic brain injury, multiple sclerosis (MS), hypoxicischemic encephalopathy, Parkinson͛s disease, schizophrenia, mood disorders.

This PhD by Publication thesis is a critical account of academic research based on five publications, produced between 2008 and 2017. These studies investigated the mechanisms mediating the neuroprotective and neuroreparative effects of EPO in experimental models of stroke and MS. After a general introduction, the main findings of each paper are critically summarised and discussed in the context of previous and subsequent literature. Specifically, the first paper describes the increase of locally produced endogenous EPO in the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. The manuscript discusses the role of endogenous EPO in the response to injury and the possibility of inducing its production for therapeutic purposes. The subsequent four papers explore the mechanisms mediating the protective action of EPO in cerebral ischemia in rats, a model of ischemic stroke, and in the murine EAE model, building upon previous findings highlighting the therapeutic efficacy of exogenously administered EPO in these models. In these studies, DNA microarray analysis and real time reverse transcription quantitative PCR (RT-qPCR) revealed an induction of a set of genes involved in neuronal plasticity and myelination in the cortex of rats with cerebral ischemia. The myelinating effects of EPO and the underlying mechanisms were then investigated in vitro, using a rat oligodendrocyte cell line.

Taken all together, the papers presented in this thesis have contributed to the characterisation of the mechanisms mediating the neuroprotective and neuroreparative effects of EPO. The data have highlighted the contribution of reparative mechanisms, including increased neuronal plasticity and myelination, that might help to explain the longterm protective effects of EPO in diverse models of injury and disease of the nervous system.

Date of Award	2021
Original language	English
Awarding Institution	University of Brighton
Supervisor	Sandra Sacre (Supervisor)

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Links

Endogenous Erythropoietin as Part of the Cytokine Network in the Pathogenesis of Experimental Autoimmune Encephalomyelitis. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/2.0)

Erythropoietin-induced changes in brain gene expression reveal induction of synaptic plasticity genes in experimental stroke

Erythropoietin Does Not Affect TNF and IL-6 Production Directly

Erythropoietin (EPO) Increases Myelin Gene Expression in CG4 Oligodendrocyte Cells through the Classical EPO Receptor. This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

Erythropoietin Increases Myelination in Oligodendrocytes: Gene Expression Profiling Reveals Early Induction of Genes Involved in Lipid Transport and Metabolism. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.