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

作者：David Devos, Caroline Moreau, Jean Christophe Devedjian, Jérôme Kluza, Maud Pétrault, Charlotte Laloux, Aurélie Jonneaux, Gilles Ryckewaert, Guillaume Garçon, Nathalie Rouaix, Alain Duhamel, Patrice Jissendi, Kathy Dujardin, F. Auger, Laura Ravasi, Lucie Hopes, Guillaume Grolez, Wance J. J. Firdaus, Bernard Sablonnière, Isabelle Strubi-Vuillaume, Noël Zahr, A. Destée, Jean‐Christophe Corvol, Dominik Pöltl, Marcel Leist, Christian Rosé, Luc Defebvre, Philippe Marchetti, Zvi Ioav Cabantchik, Régis Bordet · 发表于：Antioxidants and Redox Signaling · 年份：2013 · DOI：10.1089/ars.2013.5593 · 被引用次数：629 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Neurological disorders and treatments、Hemoglobinopathies and Related Disorders

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, respecti...