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

Devos, David; MoreauCaroline,; Christophe, DevedjianJean; Kluza, Jérôme; PetraultMaud,; Laloux, Charlotte; JonneauxAurélie,; RyckewaertGilles,; GarçonGuillaume,; RouaixNathalie,; DuhamelAlain,; JissendiPatrice,; DujardinKathy,; AugerFlorent,; RavasiLaura,; HopesLucie,; GrolezGuillaume,; FirdausWance,; SablonnièreBernard,; Strubi-VuillaumeIsabelle,; ZahrNoel,; DestéeAlain,; Corvol, Jean‐Christophe; PöltlDominik,; Leist, Marcel; RoseChristian,; DefebvreLuc,; Marchetti, Philippe; Ioav, CabantchikZ.; BordetRégis,

doi:10.1089/ars.2013.5593

Cited by 517 publications

(511 citation statements)

References 73 publications

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“…A direct relationship between total iron (in the plasma) and labile iron pool (in the cells) is evident in experimental or clinical systemic iron overload, where the benefits obtained with a cell-permeant iron chelator confirm the pathological relevance of non-ferritin bound iron (Pennell et al 2011). Even though the generating mechanisms of brain siderosis are different, the same setting may be found in it, as suggested by the promising results obtained by targeting chelatable iron with deferiprone in an experimental model of PD and in early-stage PD patients (Devos et al 2014). Important aspects in this possible pathogenic mechanisms are not clear yet; in particular, what is the difference between iron accumulation in normal ageing and in neurodegenerative disorders with brain iron overload?…”

Section: Ferritin In Brain Disorders With Altered Iron Homeostasismentioning

confidence: 94%

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

2014

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Iron is an abundant transition metal that is essential for life, being associated to many enzyme and oxygen carrier proteins involved in a variety of fundamental cellular processes. At the same time the metal is potentially toxic due to its capacity to engage in the catalytic production of noxious reactive oxygen species. The control of iron availability in the cells is largely dependent on ferritins, ubiquitous proteins with storage and detoxification capacity. In mammals, cytosolic ferritins are composed of two types of subunits, the H and the L chain, assembled to form a 24-mer spherical cage. Ferritin is present also in mitochondria, in the form of a complex with 24 identical chains. Even though the proteins have been known for a long time, their study is a very active and interesting field yet. In this review we will focus our attention to mammalian cytosolic and mitochondrial ferritins, describing the most recent advancement regarding their storage and antioxidant function, the effects of their genetic mutations in human pathology, and also the possible involvement in non-iron related activities. We will also discuss recent evidence connecting ferritins and the toxicity of iron in a set of neurodegenerative disorder characterized by focal cerebral siderosis. IntroductionThe adaptation of life to an oxic environment required the development of mechanisms to deal with the transformation of the water soluble ferrous ion (Fe 2+ ) to the insoluble ferric ion (Fe 3+ ) and with the concomitant generation of dangerous reactive oxygen species (ROS). The ferritin molecules represent an important and ancient mean developed by organisms in the three domains of life to safely handle the necessary, yet potentially toxic metal. Their ability to detoxify and store the metal through safe oxidation processes protects the cells from undue iron-dependent redox chemistry, while a controlled release of the metal guarantees its availability for different and essential enzymatic reactions. Storage and detoxification of iron represent the main functions of these molecules, and much work has been done to understand the chemical and molecular details of this

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Section: Ferritin In Brain Disorders With Altered Iron Homeostasismentioning

confidence: 94%

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

2014

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“…This encouraging trial data has not led to further AD clinical development of compounds that target iron. However, a recent Parkinson's disease clinical trial of the iron chelator, deferiprone, showed improvement in motor function over an 18-month period [222].…”

Section: Iron Chelatorsmentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

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“…Results indicated that the early start group (who started deferiprone six months earlier) had a slower disease progression on the 18 month-follow up visit as documented by a 2.4 points lower motor score in the Unified PD Rating Scale (UPDRS-III). Additionally, iron content in the SN, as well as malonaldehyde, carbonyl-proteins and 8-oxdG in the CSF were significantly decreased compared to baseline [134]. Patients with lower ceruloplasmin activity in the CSF appeared to respond better to iron chelation suggesting that ceruloplasmin may modify the response to deferiprone treatment in PD [135].…”

Section: Parkinson's and Alzheimer's Diseasesmentioning

confidence: 89%

Iron chelation in the treatment of neurodegenerative diseases

Dušek

Schneider

Aaseth

2016

Journal of Trace Elements in Medicine and Biology

106

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a b s t r a c tDisturbance of cerebral iron regulation is almost universal in neurodegenerative disorders. There is a growing body of evidence that increased iron deposits may contribute to degenerative changes. Thus, the effect of iron chelation therapy has been investigated in many neurological disorders including rare genetic syndromes with neurodegeneration with brain iron accumulation as well as common sporadic disorders such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis. This review summarizes recent advances in understanding the role of iron in the etiology of neurodegeneration. Outcomes of studies investigating the effect of iron chelation therapy in neurodegenerative disorders are systematically presented in tables. Iron chelators, particularly the blood brain barrier-crossing compound deferiprone, are capable of decreasing cerebral iron in areas with abnormally high concentrations as documented by MRI. Yet, currently, there is no compelling evidence of the clinical effect of iron removal therapy on any neurological disorder. However, several studies indicate that it may prevent or slow down disease progression of several disorders such as aceruloplasminemia, pantothenate kinase-associated neurodegeneration or Parkinson's disease.

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

Abstract: 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.

Cited by 517 publications

References 73 publications

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

Biometals and Their Therapeutic Implications in Alzheimer's Disease

Iron chelation in the treatment of neurodegenerative diseases

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