Devos David, Moreau Caroline, Devedjian Jean Christophe, Kluza Jérome, Petrault Maud, Laloux Charlotte, Jonneaux Aurélie, Ryckewaert Gilles, Garçon Guillaume, Rouaix Nathalie, Duhamel Alain, Jissendi Patrice, Dujardin Kathy, Auger Florent, Ravasi Laura, Hopes Lucie, Grolez Guillaume, Firdaus Wance, Sablonnière Bernard, Strubi-Vuillaume Isabelle, Zahr Noel, Destée Alain, Corvol Jean-Christophe, Pöltl Dominik, Leist Marcel, Rose Christian, Defebvre Luc, Marchetti Philippe, Cabantchik Z Ioav, Bordet Régis
1 Department of Medical Pharmacology, Faculté de Médecine Lille2, Lille Nord de France University , CHU Lille, Lille, France .
Antioxid Redox Signal. 2014 Jul 10;21(2):195-210. doi: 10.1089/ars.2013.5593. Epub 2014 Feb 6.
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.
通过一种螯合策略评估铁在帕金森病（PD）中的病理生理作用，该策略旨在减少与局部铁沉积相关的氧化损伤，同时不影响循环金属。转化细胞和动物模型提供了概念验证以及延迟启动（DS）治疗模式，这是初步临床评估的基础。
在转化研究中，我们通过跟踪运动功能、纹状体多巴胺（高效液相色谱法和磁共振成像 - 正电子发射断层扫描）以及脑铁沉积（弛豫 - R2磁共振成像）来评估经去铁酮（DFP）全身预螯合的小鼠受到氧化损伤后的情况，同时借助神经元不稳定铁的光谱测量（使用荧光敏感铁传感器）以及蛋白质、脂质和DNA修饰标志物来评估氧化损伤。DFP显著降低了氧化应激细胞和动物中的不稳定铁及生物损伤，改善了运动功能，同时提高了纹状体多巴胺水平。在一项试点双盲、安慰剂对照随机临床试验中，处于多巴胺治疗稳定期的早期帕金森病患者参加了一项为期12个月的单中心研究，使用DFP（30毫克/千克/天）。基于6个月的DS模式，早期开始治疗的患者（n = 19）与DS患者（n = 18）（40例中有37例完成研究）相比，在黑质铁沉积（R2磁共振成像）和帕金森病统一评分量表疾病进展的运动指标方面，对治疗的反应显著更早且更持久（分别为p < 0.03和p < 0.04）。除了3例迅速缓解的中性粒细胞减少病例外，整个试验期间安全性良好。
一种避免全身铁水平变化的适度铁螯合方案可能构成PD的一种新型治疗方式。
在转化模型和试点临床试验中确立的螯合方式的治疗特性，值得对螯合在PD中的症状缓解和/或疾病修饰潜力进行全面评估。
