TY - JOUR
T1 - Targeting chelatable iron as a therapeutic modality in Parkinson's disease
AU - Devos, David
AU - Moreau, Caroline
AU - Devedjian, Jean Christophe
AU - Kluza, Jérome
AU - Petrault, Maud
AU - Laloux, Charlotte
AU - Jonneaux, Aurélie
AU - Ryckewaert, Gilles
AU - Garçon, Guillaume
AU - Rouaix, Nathalie
AU - Duhamel, Alain
AU - Jissendi, Patrice
AU - Dujardin, Kathy
AU - Auger, Florent
AU - Ravasi, Laura
AU - Hopes, Lucie
AU - Grolez, Guillaume
AU - Firdaus, Wance
AU - Sablonnière, Bernard
AU - Strubi-Vuillaume, Isabelle
AU - Zahr, Noel
AU - Destée, Alain
AU - Corvol, Jean Christophe
AU - Pöltl, Dominik
AU - Leist, Marcel
AU - Rose, Christian
AU - Defebvre, Luc
AU - Marchetti, Philippe
AU - Cabantchik, Z. Ioav
AU - Bordet, Régis
PY - 2014/7/10
Y1 - 2014/7/10
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84897930725
U2 - 10.1089/ars.2013.5593
DO - 10.1089/ars.2013.5593
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C2 - 24251381
AN - SCOPUS:84897930725
SN - 1523-0864
VL - 21
SP - 195
EP - 210
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 2
ER -