Could Conservative Iron Chelation Lead to Neuroprotection in Amyotrophic Lateral Sclerosis?© Caroline Moreau et al. 2018; Published by Mary Ann Liebert, Inc. This Open Access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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. Antioxid. Redox Signal. 29, 742–748.

Oxidative Stress, Neuroinflammation and Mitochondria in the Pathophysiology of Amyotrophic Lateral Sclerosis

“…Based on available evidences and the pathophysiology mechanisms described above, we might suggest other options to be also explored, i.e., therapeutic agents to control the intracellular glutamate cytotoxicity (e.g., necrostatin-1) [ 109 , 110 ]; anti-inflammatory drugs [ 111 , 112 ]; specific cannabinoid receptors such as CB2 (to improve neuroprotection) [ 113 ]; metal chelators, e.g., the iron chelator deferiprone (to limit metal-induced toxicity leading to OS) [ 114 ]; neurotrophins (to promote neuroplasticity) [ 115 ]; cyclic nucleotide phosphodiesterase (PDE) inhibitors to prevent glial cell activation (e.g., ibudilast) [ 116 ]; antiretrovirals (e.g., TRIUMEQ ® , a combination of abacavir sulfate, dolutegravir sodium, and lamivudine) used as an anti-HIV therapy, and based on the fact that ALS patients present serum concentrations of reverse transcriptase comparable to HIV-infected patients [ 117 ]; antiepileptic drugs (e.g., retigabine, which acts by binding to the voltage-gated K + channels and increasing the M-current, thus leading to membrane hyperpolarization and decreasing excitability) [ 118 ]; or the antiestrogen tamoxifen (some neurological improvements have been observed in ALS patients with breast cancer and treated with tamoxifen—an effect possibly related to the inhibition of protein kinase C, which is overexpressed in the spinal cord of ALS patients) (see e.g., NCT00214110 under ).…”

The Aging of Iron Man

“…The recent deferiprone clinical trials in PD (Devos et al, 2014 ) and amyotrophic lateral sclerosis (Martin-Bastida et al, 2017 ; Moreau et al, 2017 ) were well tolerated and showed reductions in brain iron load, and was associated with improved clinical performance, and a better quality of life. However, there is increased incidence of agranulocytosis with deferiprone (Tricta et al, 2016 ) and there is a need to develop second generation of iron chelators without this side-effect (Xie et al, 2016 ).…”

The Dual Role of Hepcidin in Brain Iron Load and Inflammation

“…In other diseases accompanied with neurodegeneration (Huntington disease, amyotrophic lateral sclerosis) iron deposition is also increased in different brain structures ( Chen et al, 2013 ; Muller and Leavitt, 2014 ; Szeliga et al, 2016 ; Moreau et al, 2018 ). Changes in expression of iron protein carriers and the therapeutic potential of iron chelation evoke striking similarities with AD and PD ( Salazar et al, 2008 ; Zheng et al, 2009 ; Chen et al, 2013 ; Belaidi and Bush, 2016 ; Szeliga et al, 2016 ; Moreau et al, 2018 ). It is speculative to suggest that the role of hepcidin in neurodegenerative diseases might be of primary importance, due to the dominating role of innate immune system in the pathophysiology of these diseases.…”

“…In animal models with PD neurodegeneration is associated with increased microglial activity and FPN downregulation ( Zhang et al, 2014 ). In addition, human trials with iron chelators have shown promise in retarding the progress of neuronal damage ( Crapper McLachlan et al, 1991 ; Martin-Bastida et al, 2017 ; Moreau et al, 2018 ). But, long-term results of this therapy are still unknown and pending future trials ( Adlard and Bush, 2018 ).…”