Targeting Chelatable Iron As a Therapeutic Modality in Parkinson's Disease

Overview

Journal Antioxid Redox Signal

Specialty Endocrinology

Date 2013 Nov 21

PMID 24251381

Citations 291

Authors

David Devos

Caroline Moreau

Jean Christophe Devedjian

Jerome Kluza

Maud Petrault

Charlotte Laloux

Aurelie Jonneaux

Gilles Ryckewaert

Guillaume Garcon

Nathalie Rouaix

Alain Duhamel

Patrice Jissendi

Kathy Dujardin

Florent Auger

Laura Ravasi

Lucie Hopes

Guillaume Grolez

Wance Firdaus

Bernard Sablonniere

Isabelle Strubi-Vuillaume

Noel Zahr

Alain Destee

Jean-Christophe Corvol

Dominik Poltl

Marcel Leist

Christian Rose

Luc Defebvre

Philippe Marchetti

Z Ioav Cabantchik

Regis Bordet

Affiliations

Soon will be listed here.

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 (30 mg/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.

Citing Articles

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Polydatin and Nicotinamide Prevent Iron Accumulation and Lipid Peroxidation in Cellular Models of Mitochondrial Diseases.

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