Wirkungen von rekombinantem humanen Erythropoietin im Cuprizone-Maus-Modell

Neuroprotektive und neuroregenerative Eigenschaften von Erythropoietin (EPO) wurden u.a. in Modellen der experimentellen autoimmunen Enzephalomyelitis (etablierte Tiermodelle zur Untersuchung der Multiplen Sklerose (MS)) und in Patienten mit chronisch-progredienter MS nachgewiesen. Der Wirkmechanismus von EPO bei diesen Bedingungen ist allerdings noch nicht vollstErythropoietin (EPO) has potent neuroprotective/neuroregenerative properties in various forms of experimental autoimmune encephalomyelitis (EAE), i.e. established rodent models of acute multiple sclerosis (MS), and in patients suffering from chronic progressive MS. However, the mechanisms of EPO action in these conditions is still not clear. In particular, studies on potential effects of EPO on oligodendrocytes/myelin in the absence of immune-inflammatory components, which are characteristic for acute MS but not for the chronic progressive state of the disease, are lacking. Therefore, in this PhD thesis, the cuprizone mouse model was employed to investigate the effect of EPO on toxic demyelination. This model allows investigation of myelination processes independent of T-cell mediated inflammation. Feeding of mice with 0.2% cuprizone mixed into ground chow results in demyelination of the corpus callosum, whereas withdrawal of the toxin leads to spontaneous remyelination. The hypothesis of the present thesis was that EPO modulates both, cuprizone-induced demyelination and the remyelination upon toxin-withdrawal. Two study designs were chosen to investigate the effects of EPO in a clinically most relevant manner: (1) EPO treatment was started immediately after cessation of 6 weeks of cuprizone feeding, i.e. at the time point of full damage and initiation of recovery/remyelination, or (2) EPO was given after 3 weeks of toxin application and continued for 3 weeks until cessation of cuprizone feeding to catch the demyelination phase. For both study parts, a 'double-blind' (for food/injections), placebo-controlled, longitudinal 4-arm design, using 8 week old male C57BL/6 mice, was applied. Target parameters included behavioral analyses, magnetic resonance imaging, and histology, as well as measurement of protein and mRNA levels. The cuprizone mouse model emerged as a highly variable animal model, making deeper mechanistic analyses of EPO effects difficult. Despite these limitations and a lack of clear effects of EPO on remyelination, EPO showed surprisingly distinct results when applied during the demyelination phase. Immediately after termination of cuprizone feeding, EPO revealed beneficial effects on vestibulomotor function/coordination, magnetic resonance imaging readouts and inflammation, as reflected by the number of microglia in the corpus callosum. Importantly, for the first time, EPO was found to reduce axonal degeneration in brain white matter tracts. These findings are of high relevance with respect to novel treatment strategies for demyelinating diseases such as MS