Devos, D; Moreau, C; Devedjian, JC; Kluza, J; Petrault, M; Laloux, C; Jonneaux, A; Ryckewaert, G; Garcon, G; Rouaix, N; Duhamel, A; Jissendi, P; Dujardin, K; Auger, F; Ravasi, L; Hopes, L; Grolez, G; Firdaus, W; Sablonniere, B; Strubi-Vuillaume, I; Zahr, N; Destee, A; Corvol, JC; Poeltl, D; Leist, M; Rose, C; Defebvre, Luc; Marchetti, P; Cabantchik, ZI; Bordet, R
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.
