Trial of Deferiprone in Parkinson’s Disease

Devos, David; Labreuche, Julien; Rascol, Olivier; Corvol, Jean‐Christophe; Duhamel, Alain; Delannoy, Pauline Guyon; Poewe, Werner; Compta, Yaroslau; Pavese, Nicola; Růžička, Evžen; Dušek, Petr; Post, Bart; Bloem, Bastiaan R.; Berg, Daniela; Maetzler, Walter; Otto, Markus; Habert, Marie‐Odile; Lehericy, Stéphane; Ferreira, Joaquim J.; Dodel, Richard; Tranchant, Christine; Eusebio, Alexandre; Thobois, Stéphane; Marques, Ana‐Raquel; Meissner, Wassilios; Ory‐Magne, Fabienne; Walter, Uwe; Bie, Rob M.A. de; Gago, Miguel; Vilas, Dolores; Kulisevsky, Jaime; Januário, Cristina; Coelho, Miguel; Behnke, Stefanie; Worth, Paul; Seppi, Klaus; Ouk, Thavarak; Potey, Camille; Leclercq, Céline C.; Viard, R.; Kuchcinski, Grégory; Lopes, Renaud; Pruvo, Jean‐Pierre; Pigny, Pascal; Garçon, Guillaume; Simonin, O.; Carpentier, Jessica; Rolland, Anne‐Sophie; Nyholm, Dag; Scherfler, Christoph; Mangin, Jean‐François; Chupin, Marie; Bordet, Régis; Dexter, David T.; Fradette, Caroline; Spino, Michael; Tricta, Fernando; Ayton, Scott; Bush, Ashley I.; Devedjian, Jean-Christophe; Duce, James A.; Cabantchik, Ioav; Defebvre, Luc; Deplanque, Dominique; Moreau, Caroline

doi:10.1056/nejmoa2209254

Cited by 96 publications

(54 citation statements)

References 23 publications

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“…119 Independently of the role of iron in the substantia nigra and its contribution to the pathophysiology of PD, a recent trial showed that although it is possible to reduce the nigrostriatal iron content using a chelator (deferiprone), it was associated with an aggravation of parkinsonism questioning the potential benefits of such an intervention and the true role of iron in the pathogenesis of PD. 120 An alternative approach is to investigate nigral pars compacta changes profiting from paramagnetic properties of neuromelanin and using high-resolution T1-weighted images. 121 This approach has shown better diagnostic accuracy than iron nigral signal in separating PD from essential tremor and HCs, 122 and also in LRRK2 patients.…”

Section: Structural and Functional Magnetic Resonance Imagingmentioning

confidence: 99%

“…Asymptomatic carriers had values in the range of those of PD patients, suggesting that iron deposition is an early event possibly occurring in premotor PD 119 . Independently of the role of iron in the substantia nigra and its contribution to the pathophysiology of PD, a recent trial showed that although it is possible to reduce the nigrostriatal iron content using a chelator (deferiprone), it was associated with an aggravation of parkinsonism questioning the potential benefits of such an intervention and the true role of iron in the pathogenesis of PD 120 …”

Section: Current “Diagnostic” Biomarkersmentioning

confidence: 99%

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Defining the Riddle in Order to Solve It: There Is More Than One “Parkinson's Disease”

et al. 2023

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ants, as has been done and implemented for other heterogeneous neurological syndromes, such as stroke and peripheral neuropathy. We strongly advocate for a more systematic and evidence-based integration of our diverse disciplines by looking at well-defined variants of the syndrome of PD. Conclusion: Accuracy in defining endophenotypes of "typical PD" across these different but interrelated disciplines will enable better definition of variants and their stratification in therapeutic trials, a prerequisite for breakthroughs in the era of precision medicine.

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Section: Structural and Functional Magnetic Resonance Imagingmentioning

confidence: 99%

Section: Current “Diagnostic” Biomarkersmentioning

confidence: 99%

Defining the Riddle in Order to Solve It: There Is More Than One “Parkinson's Disease”

et al. 2023

Self Cite

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“…Others have reported that early PD patients actually have less iron in the SN (Du et al, 2022), suggesting that PD may start as an issue of brain iron deficiency that facilitates disease progression. This is further supported by the recent clinical trial data that deferiprone, an iron chelator, worsened symptoms in early PD patients (Devos et al, 2022). However, it remains unclear if iron dysregulation is a secondary or primary pathological disturbance in PD and what could cause the later accumulation seen as the disease progresses.…”

Section: Parkinson's Diseasementioning

confidence: 76%

Brain iron acquisition: An overview of homeostatic regulation and disease dysregulation

Baringer

Simpson

Connor

2023

Journal of Neurochemistry

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Brain iron homeostasis is crucial for neurological health, with pathological fluctuations in brain iron levels associated with a variety of neurological disorders. Low levels are connected to cognitive impairment and restless legs syndrome, while high levels are connected to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Given the detrimental effects unrestricted iron can have, regulated entry into the brain via transferrin and H‐ferritin is critical. Endothelial cells of the blood–brain barrier are the site of iron transport regulation. The movement of iron through endothelial cells into the brain can be divided into three distinct processes: uptake, transcytosis, and release. Each process possesses external and internal influences on the regulation at each stage. This review discusses the mechanisms of iron uptake, transcytosis, and release at the blood–brain barrier, as well as the elements that contribute to regulation. Additionally, we explore the dysregulation of brain iron in Alzheimer's disease, Parkinson's disease, and restless legs syndrome.

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“…Therefore, VK-28 may act at lower concentrations in the brain, making it more suitable for clinical ( Li et al, 2017a ). Deferiprone, an iron chelator that can cross the blood-brain barrier, is utilized for transfusion-dependent thalassemia as well as in Parkinson’s disease clinical trials ( Devos et al, 2022 ). These results may stimulate further development of iron chelators for ICH treatment.…”

Section: Therapeutic Applicationmentioning

confidence: 99%

Ferroptosis: Underlying mechanism and the crosstalk with other modes of neuronal death after intracerebral hemorrhage

Cao

Xiao²,

Liu³

et al. 2023

Front. Cell. Neurosci.

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Intracerebral hemorrhage (ICH) is a serious cerebrovascular disease with high rates of morbidity, mortality, and disability. Optimal treatment of ICH is a major clinical challenge, as the underlying mechanisms remain unclear. Ferroptosis, a newly identified form of non-apoptotic programmed cell death, is characterized by the iron-induced accumulation of lipid reactive oxygen species (ROS), leading to intracellular oxidative stress. Lipid ROS causes damage to nucleic acids, proteins, and cell membranes, eventually resulting in ferroptosis. In the past 10 years, ferroptosis has resulted in plenty of discoveries and breakthroughs in cancer, neurodegeneration, and other diseases. Some studies have also reported that ferroptosis does occur after ICH in vitro and in vivo and contribute to neuronal death. However, the studies on ferroptosis following ICH are still in the preliminary stage. In this review, we will summarize the current evidence on the mechanism underlying ferroptosis after ICH. And review the traditional modes of neuronal death to identify the crosstalk with ferroptosis in ICH, including apoptosis, necroptosis, and autophagy. Additionally, we also aim to explore the promising therapeutic application of ferroptosis in cell death-based ICH.

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Trial of Deferiprone in Parkinson’s Disease

Cited by 96 publications

References 23 publications

Defining the Riddle in Order to Solve It: There Is More Than One “Parkinson's Disease”

Defining the Riddle in Order to Solve It: There Is More Than One “Parkinson's Disease”

Brain iron acquisition: An overview of homeostatic regulation and disease dysregulation

Ferroptosis: Underlying mechanism and the crosstalk with other modes of neuronal death after intracerebral hemorrhage

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