Melatonin Treatment Reduces Oxidative Damage and Normalizes Plasma Pro-Inflammatory Cytokines in Patients Suffering from Charcot-Marie-Tooth Neuropathy: A Pilot Study in Three Children

Mariam Chahbouni,Tomás De Haro,Marisol Fernández-Ortiz,Antonio Molina-Carballo,Antonio Muñoz-Hoyos,Darío Acuña-Castroviejo,María López,Ana Guerra-Librero

doi:10.3390/molecules22101728

Abstract

Charcot-Marie-Tooth neuropathy (CMT) is a motor and sensory neuropathy comprising a heterogeneous group of inherited diseases. The CMT1A phenotype is predominant in the 70% of CMT patients, with nerve conduction velocity reduction and hypertrophic demyelination. These patients have elevated oxidative stress and chronic inflammation. Currently, there is no effective cure for CMT; herein, we investigated whether melatonin treatment may reduce the inflammatory and oxidative damage in CMT1A patients. Three patients, aged 8–10 years, were treated with melatonin (60 mg at 21:00 h plus 10 mg at 09:00 h), and plasma levels of lipid peroxidation (LPO), nitrites (NOx), IL-1β, IL-2, IL-6, TNF-α, INF-γ, oxidized to reduced glutathione (GSSG/GSH) ratio, and the activities of superoxide dismutase (SOD), glutathione-S transferase (GST), glutathione peroxidase (GPx), and reductase (GRd), were determined in erythrocytes at 3 and 6 months of treatment. Healthy age- and sex-matched subjects were used as controls. The results showed increased activities of SOD, GST, GPx, and GRd in CMT1A patients, which were reduced at 3 and 6 months of treatment. The GSSG/GSH ratio significantly increased in the patients, returning to control values after melatonin treatment. The inflammatory process was confirmed by the elevation of all proinflammatory cytokines measured, which were also normalized by melatonin. LPO and NOx, which also were elevated in the patients, were normalized by melatonin. The results document beneficial effects of the use of melatonin in CMT1A patients to reduce the hyperoxidative and inflammatory condition, which may correlate with a reduction of the degenerative process.

Highlights

Charcot-Marie-Tooth disease (CMT), known as Charcot-Marie-Tooth neuropathy, hereditary motor and sensory neuropathy, and peroneal muscular atrophy, is a motor and sensory neuropathy comprised of a large heterogeneous group of inherited diseases [1,2,3]
After 3 months of melatonin therapy, superoxide dismutase (SOD) activity declined to below controls, and it was further reduced at the end of the treatment
Comparable changes were found for glutathione-S transferase (GST) activity, which was increased in the patients before starting the therapy, reduced below controls at 3 months of treatment; the GST activity remained at this level to the end of the study, i.e., 3 months later (Figure 1B)

Summary

Introduction

Charcot-Marie-Tooth disease (CMT), known as Charcot-Marie-Tooth neuropathy, hereditary motor and sensory neuropathy, and peroneal muscular atrophy, is a motor and sensory neuropathy comprised of a large heterogeneous group of inherited diseases [1,2,3]. The CMT clinical phenotype is Molecules 2017, 22, 1728; doi:10.3390/molecules22101728 www.mdpi.com/journal/molecules. CMT was initially classified into two types; CMT1, in which nerve conduction velocities (NCVs) are reduced together with hypertrophic demyelination, is predominant in the 70% of CMT patients, and CMT2, with normal NCVs and axonopathy [1,5]. CMT is monogenic and more than 80 genes have been identified in relation with this disease [6]. The duplication of the gene coding for the peripheral myelin protein 22 on chromosome 17p11.2, is responsible for the CMT1A phenotype cursing with demyelinating and slow NCVs [7]. There is no effective cure for CMT, and only controlling the progress of the disease, physical therapy, and orthopedic treatment, are available to date. Diagnosis can facilitate the CMT patients to modify their lifestyles to minimize the damage to the nerves to delay or prevent disability

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