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Targeting chelatable iron as a therapeutic modality in Parkinson's disease

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Targeting chelatable iron as a therapeutic modality in Parkinson's disease

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DEVOS, David, Dominik PÖLTL, Marcel LEIST, 2014. Targeting chelatable iron as a therapeutic modality in Parkinson's disease. In: Antioxidants & Redox Signaling. 21(2), pp. 195-210. ISSN 1523-0864. eISSN 1557-7716. Available under: doi: 10.1089/ars.2013.5593

@article{Devos2014Targe-29753, title={Targeting chelatable iron as a therapeutic modality in Parkinson's disease}, year={2014}, doi={10.1089/ars.2013.5593}, number={2}, volume={21}, issn={1523-0864}, journal={Antioxidants & Redox Signaling}, pages={195--210}, author={Devos, David and Pöltl, Dominik and Leist, Marcel} }

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 (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. 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. Devos, David 2015-02-04T09:17:06Z Devos, David 2014 Leist, Marcel Targeting chelatable iron as a therapeutic modality in Parkinson's disease 2015-02-04T09:17:06Z terms-of-use Pöltl, Dominik Pöltl, Dominik eng Leist, Marcel

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