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

来源：

ANTIOXIDANTS & REDOX SIGNALING | 2014年 / 21卷 / 02期

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

页码：195 / 210

页数：16

共 75 条

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