18 The Open Drug Discovery Journal, 2010, 2, 18-24 1877-3818/10 2010 Bentham Open Open Access Review: Friedreich Ataxia and Erythropoietin Sylvia Boesch *,1 , Brigitte Sturm 2 , Wolfgang Nachbauer 1 , Sascha Hering 1 , Hannes Steinkellner 2 , Rainer Schneider 3 , Werner Poewe 1 and Barbara Scheiber-Mojdehkar 2 1 Department of Neurology, Anichstr. 35, Innsbruck Medical University, A-6020 Innsbruck, Austria 2 Department of Medical Chemistry, Waehringerstr. 10, Medical University of Vienna, A-1090 Vienna, Austria 3 Institute of Biochemistry and Center for Molecular Biosciences, Innsbruck, Leopold Franzens University, A-6020 Innsbruck, Austria Abstract: In vitro and in vivo studies have provided evidence for neuroprotective properties of Erythropoietin in neurodegenerative disorders. Although the magnitude of effect is still controversial, very recent findings point to neuronal protection in the central nervous system by Erythropoietins. Erythropoietin is a powerful growth factor which enhances cellular size and ultimatively increases the number of mitochondria. Friedreich Ataxia (FA), an inherited neurodegenerative disorder is caused by a loss of function mutation in the first intron on chromosome 9. FA patients therefore suffer a marked reduction of Frataxin, a mitochondrial protein which is involved in mitochondrial iron homeostasis and/or assembly of iron-sulfur (FeS) proteins and heme synthesis. Mitochondrial dysfunction results in a deleterious energy deficit especially in tissues highly dependent on oxidative phosphorylation such as neurons, muscle cells or pancreatic insular cells. Beneficial effects of recombinant human Erythropoietin (rhuEPO) may derive from an increase in Frataxin levels through currently unknown post-transcriptional and/or post-translational mechanisms. Moreover, additional effects via BDNF and through mitochondrial iron chelation may complete the spectrum of rhuEPOs actions in FA and may be part of its beneficial treatment effects. However, there are clear limitations to chronic rhuEPO treatment. Apart from hematopoietic side effects, tumor growth may be enhanced by rhuEPO application. In this review we provide an overview of studies using rhuEPO in FA and discuss potential beneficial effects of Erythropoietin in FA. Keywords: Friedreich ataxia, erythropoietin, neuroprotection, mitochondria, iron metabolism. INTRODUCTION Friedreich Ataxia (FA) is the most common inherited ataxia. FA is characterized by multiple symptoms including progressive spinocerebellar ataxia, diabetes mellitus and hypertrophic cardiomyopathy [1]. It is caused by a GAA- trinucleotide expansion in the Frataxin gene located on chromosome locus 9q13, which results in a reduced expression of Frataxin, a small mitochondrial protein [2]. Frataxin’s exact physiological function of is unknown, but it may be involved in mitochondrial iron homeostasis and/or assembly of iron-sulfur (FeS) proteins and heme synthesis [3]. Intramitochondrial iron accumulation has been postulated to initiate the production of hydroxyl radicals by the Fenton reaction, leading to inactivation of FeS enzymes, lipid peroxidation and damage to nucleic acids, proteins and ultimately resulting in cell death. Intramitochondrial iron accumulation is found in heart, liver, nervous system and spleen of FA patients [4]. Moreover, there is a reduction of mitochondrial DNA, the FeS cluster-containing subunits of the mitochondrial electron transport chain (complex I-III) and of the enzyme aconitase. *Address correspondence to this author at the Department of Neurology, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria; Tel: 0043 512 504 81815; Fax: 0043 512 504 26286; E-mail: Sylvia.Boesch@i-med.ac.at Although there is not an effective treatment for FA yet, the improved understanding of the role of Frataxin has led to the consideration of antioxidants and iron chelators as potential therapeutic agents. These drugs may have a potential to reduce some clinical features of FA, although they cannot cure the disease itself. Substances like hemin, butyric acid, 3–nitroproprionic acid or cisplatin that result in an increase in Frataxin levels have been considered a further potential approach to FA treatment [5-7]. ERYTHROPOIETIN Erythropoietin has received considerable attention because it was found to exert neuroprotective effects by a still poorly understood mechanism [8]. It has been known for a long time that Erythropoietin signaling plays a key role in bone marrow erythrocyte proliferation and hemoglobin synthesis. In response to low oxygen or ischemic events, Hypoxia Inducible Factor (HIF) regulates the expression of a number of critical hypoxia-inducible genes including that for Erythropoietin [9]. The actions of Erythropoietin in neuroprotection, independent of changes in erythrocyte synthesis, are supposed to be due to several different mechanisms [10]. First, Erythropoietin can act within the in vivo context to reverse vasospasm [11, 12], protect vascular endothelial cells [13], modulate inflammation [14] and recruit stem cells [15]. Second, Erythropoietin can act directly on neurons. It is supposed to attenuate the