title: Targeting chelatable iron as a therapeutic modality in Parkinson's disease.
abstract: OBJECTIVE
  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, respectively). Apart from three rapidly resolved neutropenia cases, safety was maintained throughout the trial.
  
  
  METHODS
  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.
authors.affiliation: 1 Department of Medical Pharmacology, Faculté de Médecine Lille2, Lille Nord de France University , CHU Lille, Lille, France .
authors.forename: David
authors.initials: D
authors.lastname: Devos
authors.forename: Caroline
authors.initials: C
authors.lastname: Moreau
authors.forename: Jean Christophe
authors.initials: JC
authors.lastname: Devedjian
authors.forename: Jérome
authors.initials: J
authors.lastname: Kluza
authors.forename: Maud
authors.initials: M
authors.lastname: Petrault
authors.forename: Charlotte
authors.initials: C
authors.lastname: Laloux
authors.forename: Aurélie
authors.initials: A
authors.lastname: Jonneaux
authors.forename: Gilles
authors.initials: G
authors.lastname: Ryckewaert
authors.forename: Guillaume
authors.initials: G
authors.lastname: Garçon
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rouaix
authors.forename: Alain
authors.initials: A
authors.lastname: Duhamel
authors.forename: Patrice
authors.initials: P
authors.lastname: Jissendi
authors.forename: Kathy
authors.initials: K
authors.lastname: Dujardin
authors.forename: Florent
authors.initials: F
authors.lastname: Auger
authors.forename: Laura
authors.initials: L
authors.lastname: Ravasi
authors.forename: Lucie
authors.initials: L
authors.lastname: Hopes
authors.forename: Guillaume
authors.initials: G
authors.lastname: Grolez
authors.forename: Wance
authors.initials: W
authors.lastname: Firdaus
authors.forename: Bernard
authors.initials: B
authors.lastname: Sablonnière
authors.forename: Isabelle
authors.initials: I
authors.lastname: Strubi-Vuillaume
authors.forename: Noel
authors.initials: N
authors.lastname: Zahr
authors.forename: Alain
authors.initials: A
authors.lastname: Destée
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Corvol
authors.forename: Dominik
authors.initials: D
authors.lastname: Pöltl
authors.forename: Marcel
authors.initials: M
authors.lastname: Leist
authors.forename: Christian
authors.initials: C
authors.lastname: Rose
authors.forename: Luc
authors.initials: L
authors.lastname: Defebvre
authors.forename: Philippe
authors.initials: P
authors.lastname: Marchetti
authors.forename: Z Ioav
authors.initials: ZI
authors.lastname: Cabantchik
authors.forename: Régis
authors.initials: R
authors.lastname: Bordet
mesh_terms: D000818:Animals; D002460:Cell Line; D003131:Combined Modality Therapy; D000077543:Deferiprone; D004195:Disease Models, Animal; D004311:Double-Blind Method; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism*; D010865:Pilot Projects; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D007502:Iron Chelating Agents; D011728:Pyridones; D000077543:Deferiprone; D007501:Iron