TY - JOUR
T1 - Could Conservative Iron Chelation Lead to Neuroprotection in Amyotrophic Lateral Sclerosis?
AU - Moreau, Caroline
AU - Danel, Véronique
AU - Devedjian, Jean Christophe
AU - Grolez, Guillaume
AU - Timmerman, Kelly
AU - Laloux, Charlotte
AU - Petrault, Maud
AU - Gouel, Flore
AU - Jonneaux, Aurélie
AU - Dutheil, Mary
AU - Lachaud, Cédrick
AU - Lopes, Renaud
AU - Kuchcinski, Grégory
AU - Auger, Florent
AU - Kyheng, Maeva
AU - Duhamel, Alain
AU - Pérez, Thierry
AU - Pradat, Pierre François
AU - Blasco, Hélène
AU - Veyrat-Durebex, Charlotte
AU - Corcia, Philippe
AU - Oeckl, Patrick
AU - Otto, Markus
AU - Dupuis, Luc
AU - Garçon, Guillaume
AU - Defebvre, Luc
AU - Cabantchik, Z. Ioav
AU - Duce, James
AU - Bordet, Régis
AU - Devos, David
N1 - Publisher Copyright:
© Caroline Moreau et al..
PY - 2018/9/10
Y1 - 2018/9/10
N2 - Iron accumulation has been observed in mouse models and in both sporadic and familial forms of amyotrophic lateral sclerosis (ALS). Iron chelation could reduce iron accumulation and the related excess of oxidative stress in the motor pathways. However, classical iron chelation would induce systemic iron depletion. We assess the safety and efficacy of conservative iron chelation (i.e., chelation with low risk of iron depletion) in a murine preclinical model and pilot clinical trial. In Sod1G86R mice, deferiprone increased the mean life span compared with placebo. The safety was good, without anemia after 12 months of deferiprone in the 23 ALS patients enrolled in the clinical trial. The decreases in the ALS Functional Rating Scale and the body mass index were significantly smaller for the first 3 months of deferiprone treatment (30 mg/kg/day) than for the first treatment-free period. Iron levels in the cervical spinal cord, medulla oblongata, and motor cortex (according to magnetic resonance imaging), as well as cerebrospinal fluid levels of oxidative stress and neurofilament light chains were lower after deferiprone treatment. Our observation leads to the hypothesis that moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality of neuroprotection for ALS.
AB - Iron accumulation has been observed in mouse models and in both sporadic and familial forms of amyotrophic lateral sclerosis (ALS). Iron chelation could reduce iron accumulation and the related excess of oxidative stress in the motor pathways. However, classical iron chelation would induce systemic iron depletion. We assess the safety and efficacy of conservative iron chelation (i.e., chelation with low risk of iron depletion) in a murine preclinical model and pilot clinical trial. In Sod1G86R mice, deferiprone increased the mean life span compared with placebo. The safety was good, without anemia after 12 months of deferiprone in the 23 ALS patients enrolled in the clinical trial. The decreases in the ALS Functional Rating Scale and the body mass index were significantly smaller for the first 3 months of deferiprone treatment (30 mg/kg/day) than for the first treatment-free period. Iron levels in the cervical spinal cord, medulla oblongata, and motor cortex (according to magnetic resonance imaging), as well as cerebrospinal fluid levels of oxidative stress and neurofilament light chains were lower after deferiprone treatment. Our observation leads to the hypothesis that moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality of neuroprotection for ALS.
KW - amyotrophic lateral sclerosis
KW - conservative iron chelator
KW - neuroprotection
KW - oxidative stress
KW - treatment
UR - http://www.scopus.com/inward/record.url?scp=85051020714&partnerID=8YFLogxK
U2 - 10.1089/ars.2017.7493
DO - 10.1089/ars.2017.7493
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C2 - 29287521
AN - SCOPUS:85051020714
SN - 1523-0864
VL - 29
SP - 742
EP - 748
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 8
ER -