Targeting chelatable iron as a therapeutic modality in Parkinson's disease

David Devos*, Caroline Moreau, Jean Christophe Devedjian, Jérome Kluza, Maud Petrault, Charlotte Laloux, Aurélie Jonneaux, Gilles Ryckewaert, Guillaume Garçon, Nathalie Rouaix, Alain Duhamel, Patrice Jissendi, Kathy Dujardin, Florent Auger, Laura Ravasi, Lucie Hopes, Guillaume Grolez, Wance Firdaus, Bernard Sablonnière, Isabelle Strubi-VuillaumeNoel Zahr, Alain Destée, Jean Christophe Corvol, Dominik Pöltl, Marcel Leist, Christian Rose, Luc Defebvre, Philippe Marchetti, Z. Ioav Cabantchik, Régis Bordet

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

508 Scopus citations

Abstract

Aims: The pathophysiological role of iron in Parkinson's disease (PD) was assessed by a chelation strategy aimed at reducing oxidative damage associated with regional iron deposition without affecting circulating metals. Translational cell and animal models provided concept proofs and a delayed-start (DS) treatment paradigm, the basis for preliminary clinical assessments. Results: For translational studies, we assessed the effect of oxidative insults in mice systemically prechelated with deferiprone (DFP) by following motor functions, striatal dopamine (HPLC and MRI-PET), and brain iron deposition (relaxation-R2*-MRI) aided by spectroscopic measurements of neuronal labile iron (with fluorescence-sensitive iron sensors) and oxidative damage by markers of protein, lipid, and DNA modification. DFP significantly reduced labile iron and biological damage in oxidation-stressed cells and animals, improving motor functions while raising striatal dopamine. For a pilot, double-blind, placebo-controlled randomized clinical trial, early-stage Parkinson's patients on stabilized dopamine regimens enrolled in a 12-month single-center study with DFP (30mg/kg/day). Based on a 6-month DS paradigm, early-start patients (n=19) compared to DS patients (n=18) (37/40 completed) responded significantly earlier and sustainably to treatment in both substantia nigra iron deposits (R2* MRI) and Unified Parkinson's Disease Rating Scale motor indicators of disease progression (p<0.03 and p<0.04, respectively). Apart from three rapidly resolved neutropenia cases, safety was maintained throughout the trial. Innovation: A moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality for PD. Conclusions: The therapeutic features of a chelation modality established in translational models and in pilot clinical trials warrant comprehensive evaluation of symptomatic and/or disease-modifying potential of chelation in PD. Antioxid. Redox Signal. 21, 195-210.

Original languageEnglish
Pages (from-to)195-210
Number of pages16
JournalAntioxidants and Redox Signaling
Volume21
Issue number2
DOIs
StatePublished - 10 Jul 2014

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