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

ABSTRACT: 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.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.A moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality for PD.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.

SUBMITTER: Devos D

PROVIDER: S-EPMC4060813 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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

Devos David D Moreau Caroline C Devedjian Jean Christophe JC Kluza Jérome J Petrault Maud M Laloux Charlotte C Jonneaux Aurélie A Ryckewaert Gilles G Garçon Guillaume G Rouaix Nathalie N Duhamel Alain A Jissendi Patrice P Dujardin Kathy K Auger Florent F Ravasi Laura L Hopes Lucie L Grolez Guillaume G Firdaus Wance W Sablonnière Bernard B Strubi-Vuillaume Isabelle I Zahr Noel N Destée Alain A Corvol Jean-Christophe JC Pöltl Dominik D Leist Marcel M Rose Christian C Defebvre Luc L Marchetti Philippe P Cabantchik Z Ioav ZI Bordet Régis R

Antioxidants & redox signaling 20140206 2

<h4>Aims</h4>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.<h4>Results</h4>For translational studies, we assessed the effect of oxidative insults in mice systemically prechelated ...[more]

PMID: 24251381

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Project description:Plasma non-transferrin bound iron refers to heterogeneous plasma iron species, not bound to transferrin, which appear in conditions of iron overload and ineffective erythropoiesis. The clinical utility of non-transferrin bound iron in predicting complications from iron overload, or response to chelation therapy remains unproven. We undertook carefully timed measurements of non-transferrin bound iron to explore the origin of chelatable iron and to predict clinical response to deferiprone.Non-transferrin bound iron levels were determined at baseline and after 1 week of chelation in 32 patients with thalassemia major receiving deferiprone alone, desferrioxamine alone, or a combination of the two chelators. Samples were taken at baseline, following a 2-week washout without chelation, and after 1 week of chelation, this last sample being taken 10 hours after the previous evening dose of deferiprone and, in those receiving desferrioxamine, 24 hours after cessation of the overnight subcutaneous infusion. Absolute or relative non-transferrin bound iron levels were related to transfusional iron loading rates, liver iron concentration, 24-hour urine iron and response to chelation therapy over the subsequent year.Changes in non-transferrin bound iron at week 1 were correlated positively with baseline liver iron, and inversely with transfusional iron loading rates, with deferiprone-containing regimens but not with desferrioxamine monotherapy. Changes in week 1 non-transferrin bound iron were also directly proportional to the plasma concentration of deferiprone-iron complexes and correlated significantly with urine iron excretion and with changes in liver iron concentration over the next 12 months.The widely used assay chosen for this study detects both endogenous non-transferrin bound iron and the iron complexes of deferiprone. The week 1 increments reflect chelatable iron derived both from liver stores and from red cell catabolism. These increments correlate with urinary iron excretion and the change in liver iron concentration over the subsequent year thus predicting response to deferiprone-containing chelation regimes. This clinical study was registered at clinical.trials.gov with the number NCT00350662.

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

Publications

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

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