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

被引:531
作者
Devos, David [1 ,2 ,3 ]
Moreau, Caroline [2 ,3 ]
Devedjian, Jean Christophe [3 ,4 ]
Kluza, Jerome [5 ,6 ]
Petrault, Maud [1 ,3 ]
Laloux, Charlotte [1 ,3 ]
Jonneaux, Aurelie [1 ,3 ]
Ryckewaert, Gilles [2 ,3 ]
Garcon, Guillaume [7 ]
Rouaix, Nathalie [8 ]
Duhamel, Alain [9 ]
Jissendi, Patrice [10 ]
Dujardin, Kathy [2 ,3 ]
Auger, Florent [3 ,11 ]
Ravasi, Laura [3 ,12 ]
Hopes, Lucie [2 ]
Grolez, Guillaume [2 ]
Firdaus, Wance [1 ,3 ]
Sablonniere, Bernard [8 ]
Strubi-Vuillaume, Isabelle [8 ]
Zahr, Noel [13 ]
Destee, Alain [2 ,14 ]
Corvol, Jean-Christophe [15 ]
Poeltl, Dominik [16 ,17 ]
Leist, Marcel [16 ,17 ]
Rose, Christian [18 ]
Defebvre, Luc [2 ,3 ]
Marchetti, Philippe [5 ,6 ]
Cabantchik, Z. Ioav [19 ]
Bordet, Regis [1 ,3 ]
机构
[1] Univ Lille Nord France, Fac Med Lille 2, Dept Med Pharmacol, CHRU Lille, F-59037 Lille, France
[2] Univ Lille Nord France, Dept Movement Disorders & Neurol, CHU Lille, F-59037 Lille, France
[3] Univ Lille Nord France, EA 1046, F-59037 Lille, France
[4] Univ Lille Nord France, Univ Littoral, F-59037 Lille, France
[5] Univ Lille Nord France, U837, Equipe 4, INSERM, F-59037 Lille, France
[6] Univ Lille Nord France, Fac Med, F-59037 Lille, France
[7] Fac Sci Pharmaceut & Biol Lille, Dept Toxicol Publ Hlth & Environm, EA4483, Lille, France
[8] Univ Lille Nord France, CHU Lille, Dept Mol Biol, F-59037 Lille, France
[9] Univ Lille Nord France, CHU Lille, Dept Biostat, F-59037 Lille, France
[10] Univ Lille Nord France, CHU Lille, Dept Neuroradiol, F-59037 Lille, France
[11] Univ Lille Nord France, Dept Anim Neuroradiol, F-59037 Lille, France
[12] Univ Lille Nord France, Dept Anim Nucl Med, F-59037 Lille, France
[13] Hop La Pitie Salpetriere, APHP, Dept Pharmacol, Paris, France
[14] Univ Lille Nord France, INSERM JPARC U837 6, F-59037 Lille, France
[15] Hop La Pitie Salpetriere, INSERM, CR ICM,Dept Neurol, UPMC,CNRS UMR7225,UMRS975,CIC 9503, Paris, France
[16] Univ Konstanz, Doerenkamp Zbinden Chair In Vitro Toxicol & Biome, Constance, Germany
[17] Univ Konstanz, Konstanz Res Sch Chem Biol, Constance, Germany
[18] Univ Lille Nord France, Hop St Vincent de Paul, Dept Hematol, F-59037 Lille, France
[19] Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Della Pergola Chair, Jerusalem, Israel
关键词
DELAYED-START TRIAL; INTRACELLULAR LABILE IRON; FRIEDREICH ATAXIA; NEURODEGENERATIVE DISORDERS; CLINICAL-IMPLICATIONS; DOPAMINERGIC-NEURONS; THALASSEMIA MAJOR; SUBSTANTIA-NIGRA; OXIDATIVE STRESS; DOUBLE-BLIND;
D O I
10.1089/ars.2013.5593
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:195 / 210
页数:16
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