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Antioxid Redox Signal. 2014 Jul 10;21(2):195-210. doi: 10.1089/ars.2013.5593. Epub 2014 Feb 6.

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

Author information

1
1 Department of Medical Pharmacology, Faculté de Médecine Lille2, Lille Nord de France University , CHU Lille, Lille, France .

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00943748.

PMID:
24251381
PMCID:
PMC4060813
DOI:
10.1089/ars.2013.5593
[Indexed for MEDLINE]
Free PMC Article

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