New Perspectives in Iron Chelation Therapy for the Treatment of Neurodegenerative Diseases

Abstract

Iron chelation has been introduced as a new therapeutic concept for the treatment of neurodegenerative diseases with features of iron overload. At difference with iron chelators used in systemic diseases, effective chelators for the treatment of neurodegenerative diseases must cross the blood–brain barrier. Given the promissory but still inconclusive results obtained in clinical trials of iron chelation therapy, it is reasonable to postulate that new compounds with properties that extend beyond chelation should significantly improve these results. Desirable properties of a new generation of chelators include mitochondrial destination, the center of iron-reactive oxygen species interaction, and the ability to quench free radicals produced by the Fenton reaction. In addition, these chelators should have moderate iron binding affinity, sufficient to chelate excessive increments of the labile iron pool, estimated in the micromolar range, but not high enough to disrupt physiological iron homeostasis. Moreover, candidate chelators should have selectivity for the targeted neuronal type, to lessen unwanted secondary effects during long-term treatment. Here, on the basis of a number of clinical trials, we discuss critically the current situation of iron chelation therapy for the treatment of neurodegenerative diseases with an iron accumulation component. The list includes Parkinson’s disease, Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration, Huntington disease and Alzheimer’s disease. We also review the upsurge of new multifunctional iron chelators that in the future may replace the conventional types as therapeutic agents for the treatment of neurodegenerative diseases.

Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs

“…The encouraging results obtained for this CA prompted the development of other clinical trials with Deferiprone. A search in https://clinicaltrials.gov indicated four ongoing or finished tests of this molecule for the treatment of PD, as also recently reported by Nuñez and Chana-Cuevas [79].…”

“…Despite these toxicity reports, the occurrence of a metal ion dyshomeostasis in PD has suggested to also employ MCT for the therapy of this disease and of other NDs such as corticobasal degeneration, the Westfal variant of Huntington's disease, Alzheimer's disease, Friedreich's ataxia, pantothenate kinase-associated neurodegeneration, and other neuropathologies associated with brain metal overload [12,24,78,79]. In these cases, MCT was also referred to as "metal targeting", "metal attenuating" or "metal protein attenuating" [41,80,81], in order to underline the differences occurring when MCT is employed in NDs instead of in metal overloads.…”

Iatrogenic Iron Promotes Neurodegeneration and Activates Self-protection of Neural Cells against Exogenous Iron Attacks

“…5 Aberrant iron accumulation in the brain has been reported to be associated with neurodegenerative diseases, such as Alzheimer's diseases (AD), Parkinson's diseases (PD), and Huntington diseases. [6][7][8] Oxidative stress resulting from the accumulated iron triggers neuronal death leading to neurodegeneration; 9 iron being associated with production of reactive oxygen species (ROS), which injure cellular membranes, proteins and deoxyribonucleic acid (DNA). 10 Divalent metal transporter 1 (DMT1/SLC11A2) is an H + -driven multi-metal transporter responsible for transmembrane iron transport; 11 in particular DMT1 has a principle role in transporting iron into the brain.…”

Current Biomedical Use of Copper Chelation Therapy

“…Different studies demonstrated deferiprone's ability to chelate not only iron but also copper, aluminum and zinc [73], reducing their free radical catalytic activity [74]. Moreover, multifunctional iron/copper chelating agents have been evaluated even if their clinical translation has not yet progressed [75].…”