Conservative iron chelation for neurodegenerative ...
Document type :
Article dans une revue scientifique: Article de synthèse/Review paper
PMID :
Permalink :
Title :
Conservative iron chelation for neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis.
Author(s) :
Devos, David [Auteur]
Troubles cognitifs dégénératifs et vasculaires - U1171
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Cabantchik, Z Ioav [Auteur]
Moreau, caroline [Auteur]
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Danel, Véronique [Auteur]
Mahoney-Sanchez, Laura [Auteur]
Bouchaoui, Hind [Auteur]
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Gouel, Flore [Auteur]
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Rolland, Anne-Sophie [Auteur]
Duce, James A [Auteur]
Devedjian, Jean-Christophe [Auteur]
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]

Troubles cognitifs dégénératifs et vasculaires - U1171
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Cabantchik, Z Ioav [Auteur]
Moreau, caroline [Auteur]

Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Danel, Véronique [Auteur]
Mahoney-Sanchez, Laura [Auteur]
Bouchaoui, Hind [Auteur]
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Gouel, Flore [Auteur]

Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Rolland, Anne-Sophie [Auteur]
Duce, James A [Auteur]
Devedjian, Jean-Christophe [Auteur]
Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 [TCDV]
Journal title :
Journal of Neural Transmission
Abbreviated title :
J Neural Transm (Vienna)
Volume number :
127
Pages :
189-203
Publication date :
2020-01-07
ISSN :
1435-1463
English keyword(s) :
Amyotrophic Lateral Sclerosis
Animals
Chelation Therapy
Deferiprone
Humans
Iron
Iron Chelating Agents
Parkinson Disease
Amyotrophic lateral sclerosis
Conservative iron chelation
Ferroptosis
Iron metabolism
Parkinson’s disease
Animals
Chelation Therapy
Deferiprone
Humans
Iron
Iron Chelating Agents
Parkinson Disease
Amyotrophic lateral sclerosis
Conservative iron chelation
Ferroptosis
Iron metabolism
Parkinson’s disease
HAL domain(s) :
Sciences du Vivant [q-bio]/Neurosciences [q-bio.NC]
English abstract : [en]
Focal iron accumulation associated with brain iron dyshomeostasis is a pathological hallmark of various neurodegenerative diseases (NDD). The application of iron-sensitive sequences in magnetic resonance imaging has provided ...
Show more >Focal iron accumulation associated with brain iron dyshomeostasis is a pathological hallmark of various neurodegenerative diseases (NDD). The application of iron-sensitive sequences in magnetic resonance imaging has provided a useful tool to identify the underlying NDD pathology. In the three major NDD, degeneration occurs in central nervous system (CNS) regions associated with memory (Alzheimer's disease, AD), automaticity (Parkinson's disease, PD) and motor function (amyotrophic lateral sclerosis, ALS), all of which require a high oxygen demand for harnessing neuronal energy. In PD, a progressive degeneration of the substantia nigra pars compacta (SNc) is associated with the appearance of siderotic foci, largely caused by increased labile iron levels resulting from an imbalance between cell iron import, storage and export. At a molecular level, α-synuclein regulates dopamine and iron transport with PD-associated mutations in this protein causing functional disruption to these processes. Equally, in ALS, an early iron accumulation is present in neurons of the cortico-spinal motor pathway before neuropathology and secondary iron accumulation in microglia. High serum ferritin is an indicator of poor prognosis in ALS and the application of iron-sensitive sequences in magnetic resonance imaging has become a useful tool in identifying pathology. The molecular pathways that cascade down from such dyshomeostasis still remain to be fully elucidated but strong inroads have been made in recent years. Far from being a simple cause or consequence, it has recently been discovered that these alterations can trigger susceptibility to an iron-dependent cell-death pathway with unique lipoperoxidation signatures called ferroptosis. In turn, this has now provided insight into some key modulators of this cell-death pathway that could be therapeutic targets for the NDD. Interestingly, iron accumulation and ferroptosis are highly sensitive to iron chelation. However, whilst chelators that strongly scavenge intracellular iron protect against oxidative neuronal damage in mammalian models and are proven to be effective in treating systemic siderosis, these compounds are not clinically suitable due to the high risk of developing iatrogenic iron depletion and ensuing anaemia. Instead, a moderate iron chelation modality that conserves systemic iron offers a novel therapeutic strategy for neuroprotection. As demonstrated with the prototype chelator deferiprone, iron can be scavenged from labile iron complexes in the brain and transferred (conservatively) either to higher affinity acceptors in cells or extracellular transferrin. Promising preclinical and clinical proof of concept trials has led to several current large randomized clinical trials that aim to demonstrate the efficacy and safety of conservative iron chelation for NDD, notably in a long-term treatment regimen.Show less >
Show more >Focal iron accumulation associated with brain iron dyshomeostasis is a pathological hallmark of various neurodegenerative diseases (NDD). The application of iron-sensitive sequences in magnetic resonance imaging has provided a useful tool to identify the underlying NDD pathology. In the three major NDD, degeneration occurs in central nervous system (CNS) regions associated with memory (Alzheimer's disease, AD), automaticity (Parkinson's disease, PD) and motor function (amyotrophic lateral sclerosis, ALS), all of which require a high oxygen demand for harnessing neuronal energy. In PD, a progressive degeneration of the substantia nigra pars compacta (SNc) is associated with the appearance of siderotic foci, largely caused by increased labile iron levels resulting from an imbalance between cell iron import, storage and export. At a molecular level, α-synuclein regulates dopamine and iron transport with PD-associated mutations in this protein causing functional disruption to these processes. Equally, in ALS, an early iron accumulation is present in neurons of the cortico-spinal motor pathway before neuropathology and secondary iron accumulation in microglia. High serum ferritin is an indicator of poor prognosis in ALS and the application of iron-sensitive sequences in magnetic resonance imaging has become a useful tool in identifying pathology. The molecular pathways that cascade down from such dyshomeostasis still remain to be fully elucidated but strong inroads have been made in recent years. Far from being a simple cause or consequence, it has recently been discovered that these alterations can trigger susceptibility to an iron-dependent cell-death pathway with unique lipoperoxidation signatures called ferroptosis. In turn, this has now provided insight into some key modulators of this cell-death pathway that could be therapeutic targets for the NDD. Interestingly, iron accumulation and ferroptosis are highly sensitive to iron chelation. However, whilst chelators that strongly scavenge intracellular iron protect against oxidative neuronal damage in mammalian models and are proven to be effective in treating systemic siderosis, these compounds are not clinically suitable due to the high risk of developing iatrogenic iron depletion and ensuing anaemia. Instead, a moderate iron chelation modality that conserves systemic iron offers a novel therapeutic strategy for neuroprotection. As demonstrated with the prototype chelator deferiprone, iron can be scavenged from labile iron complexes in the brain and transferred (conservatively) either to higher affinity acceptors in cells or extracellular transferrin. Promising preclinical and clinical proof of concept trials has led to several current large randomized clinical trials that aim to demonstrate the efficacy and safety of conservative iron chelation for NDD, notably in a long-term treatment regimen.Show less >
Audience :
Non spécifiée
Administrative institution(s) :
Université de Lille
Inserm
CHU Lille
Inserm
CHU Lille
Collections :
Research team(s) :
Troubles cognitifs dégénératifs et vasculaires
Submission date :
2021-06-16T06:31:30Z
2021-09-09T14:02:51Z
2021-09-09T14:02:51Z
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