AbstractErythropoietin (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|
|Supervisor||Sandra Sacre (Supervisor)|