Deferiprone targets aconitase: Implication for Fridreich’s ataxia

Inserm, U676, Hôpital Robert Debré, Paris, F-75019 France and Université Paris 7, Faculté de Médecine Denis Diderot, IFR02, Paris, France.
BMC Neurology (Impact Factor: 2.04). 02/2008; 8(1):20. DOI: 10.1186/1471-2377-8-20
Source: PubMed


Friedreich ataxia is a neurological disease originating from an iron-sulfur cluster enzyme deficiency due to impaired iron handling in the mitochondrion, aconitase being particularly affected. As a mean to counteract disease progression, it has been suggested to chelate free mitochondrial iron. Recent years have witnessed a renewed interest in this strategy because of availability of deferiprone, a chelator preferentially targeting mitochondrial iron.
Control and Friedreich's ataxia patient cultured skin fibroblasts, frataxin-depleted neuroblastoma-derived cells (SK-N-AS) were studied for their response to iron chelation, with a particular attention paid to iron-sensitive aconitase activity.
We found that a direct consequence of chelating mitochondrial free iron in various cell systems is a concentration and time dependent loss of aconitase activity. Impairing aconitase activity was shown to precede decreased cell proliferation.
We conclude that, if chelating excessive mitochondrial iron may be beneficial at some stage of the disease, great attention should be paid to not fully deplete mitochondrial iron store in order to avoid undesirable consequences.

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    • "However, these studies have to be considered along other experimental evidence suggesting that iron chelation, even by deferiprone, may be deleterious in FRDA under certain circumstances. A small study indicated that deferiprone at the concentration of 150 lM, but not at 25 lM, decreased aconitase activity in cultured fibroblasts by 70–80%, and at concentrations higher than 50 lM it could also inhibit cell proliferation (Goncalves et al. 2008). Another study demonstrated that frataxin mRNA levels decrease significantly in multiple human cell lines treated with desferoxamine (Li et al. 2008). "
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    ABSTRACT: Friedreich's ataxia (FRDA) is a neurological disease related to a deficiency of the protein frataxin involved in iron–sulfur (Fe–S) cluster biogenesis. This leads to an increased cellular iron uptake accumulating in mitochondria, and a subsequently disturbed iron homeostasis. The detailed mechanism of iron regulation of frataxin expression is yet unknown. Deferiprone, an iron chelator that may cross the blood–brain barrier, was shown to shuttle iron between subcellular compartments. It could also transfer iron from iron-overloaded cells to extracellular apotransferrin and pre-erythroid cells for heme synthesis. Here, clinical studies on Deferiprone are reviewed in the context of alternative agents such as desferoxamine, with specific regard to its mechanistic and clinical implications.
    Full-text · Article · Aug 2013 · Journal of Neurochemistry
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    • "Deferiprone or 1,2-dimethyl-3-hydroxypyrid-4-one (Figure 1) is an active iron chelator and superoxide radical scavenger which belongs to the new class of chelating agents, i.e. alpha-ketohydroxypyridines. Iron overload which can occur as a consequence of chronic transfusion therapy in patients with β-thalassemia and sickle cell diseases or due to excessive dietary iron uptake in patients with chronic anemia and hereditary hemochromatosis, causes organ damages and its chelators such as deferiprone (DFP) should be used to remove excess iron from various parts of body (1-5). Intestinal absorption of DFP and one of its analogs was investigated by Taher et al. (6). "
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    ABSTRACT: A sensitive fluorometric method for the determination of deferiprone (DFP) based on the formation of a luminescent complex with Tb(3+) ions in aqueous solutions is reported. The maximum excitation and emission wavelengths were 295 and 545 nm, respectively. The effects of various factors on the luminescence intensity of the system were investigated and optimized, then under the optimum conditions, the method was validated. The method validation results indicated that the relative intensity at 545 nm has a linear relationship with the concentration of DFP in aqueous solutions at the range of 7.2 × 10(-9) to 1.4 × 10(-5) M, the detection and quantification limits were calculated respectively as 6.3 × 10(-9) and 2.1 × 10(-8) M, precision and accuracy of the method were lower than 5% and the recovery was between 100.1% and 102.3%. The results indicated that this method was simple, time saving, specific, accurate and precise for the determination of DFP in aqueous solutions. After optimization and validation, the method successfully applied for determination of DFP in tablet dosage forms. The stoichiometry of the Tb(3+)-DFP complex was found as 1:3 and the complex formation constant was 1.6 × 10(16).
    Full-text · Article · Feb 2012 · Iranian journal of pharmaceutical research (IJPR)
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    • "Deferiprone (DFP or L1) is an oral Fe2+-specific chelating agent used to treat iron accumulation in thalassaemia. Clinical trials of treatment with L1 for Friedreich's ataxia (FA), a severe inherited neurological disease, demonstrated the elimination of labile iron deposits in a specific brain region without significant adverse changes in hemoglobin or plasma iron levels [56]. An additional advantage of L1 is its cost effectiveness, compared to DFO as it does not require the same long-term continuous dosing [57]. "
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    ABSTRACT: Dysregulation of iron metabolism has been observed in patients with neurodegenerative diseases (NDs). Utilization of several importers and exporters for iron transport in brain cells helps maintain iron homeostasis. Dysregulation of iron homeostasis leads to the production of neurotoxic substances and reactive oxygen species, resulting in iron-induced oxidative stress. In Alzheimer's disease (AD) and Parkinson's disease (PD), circumstantial evidence has shown that dysregulation of brain iron homeostasis leads to abnormal iron accumulation. Several genetic studies have revealed mutations in genes associated with increased iron uptake, increased oxidative stress, and an altered inflammatory response in amyotrophic lateral sclerosis (ALS). Here, we review the recent findings on brain iron metabolism in common NDs, such as AD, PD, and ALS. We also summarize the conventional and novel types of iron chelators, which can successfully decrease excess iron accumulation in brain lesions. For example, iron-chelating drugs have neuroprotective effects, preventing neural apoptosis, and activate cellular protective pathways against oxidative stress. Glial cells also protect neurons by secreting antioxidants and antiapoptotic substances. These new findings of experimental and clinical studies may provide a scientific foundation for advances in drug development for NDs.
    Full-text · Article · Oct 2011 · Advances in Pharmacological Sciences
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