Neurological Disorders Associated with Iron Misdistribution: The Therapeutic Potential of Siderophores

The association between iron accumulation and oxidative cell damage in specific regions of the brain has raised the possibility of using iron chelation as a therapeutic strategy in neurodegenerative disorders. In this review, Friedreich’s ataxia (FRDA) is described as a paradigm of a disorder in which cell damage is associated with misdistribution of cell iron resulting from aberrant utilization of the metal by mitochondria. Frataxin-deficient cells, serving as an in vitro model of FRDA, were used as a model for testing the effects of a chelator with the ability to sequester cell iron as well as to donate it to biological acceptors inside or outside cells (termed here a siderophore). The clinically used siderophore deferiprone (DFP) was shown to reduce mitochondrial labile iron accumulation and restore cell functions affected by frataxin deficiency. In a translation of these findings to the clinical setting, moderate doses of DFP were administered to selected patients with FRDA or neurodegeneration with brain iron accumulation (NBIA) as part of open-label studies. Treatment with DFP resulted in a significant reduction in foci of brain iron accumulation and in some functional improvements, with only minor changes in body iron stores. The prospects of using drug-mediated iron relocation vs. chelation are critically discussed in relation to other neurodegenerative disorders in which accumulated (toxic) iron has been implicated as a causative factor in regional oxidative damage, such as Parkinson’s disease or Alzheimer’s disease.