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Reduced oxidative damage in ALS by high-dose enteral melatonin treatment

Authors


  • Authors Jochen H. Weishaupt and Claudia Bartels contributed equally to this article. Authors of affiliations 1 and 2 belong to the DFG Research Centre Molecular Physiology of the Brain (CMPB)

Address reprint requests to Hannelore Ehrenreich, Division of Clinical Neuroscience, Max-Planck-Institute of Experimental Medicine, Hermann-Rein Str. 3, 37075, Göttingen, Germany.
E-mail: ehrenreich@em.mpg.de

Abstract

Abstract:  Amyotrophic lateral sclerosis (ALS) is the collective term for a fatal motoneuron disease of different etiologies, with oxidative stress as a common molecular denominator of disease progression. Melatonin is an amphiphilic molecule with a unique spectrum of antioxidative effects not conveyed by classical antioxidants. In preparation of a possible future clinical trial, we explored the potential of melatonin as neuroprotective compound and antioxidant in: (1) cultured motoneuronal cells (NSC-34), (2) a genetic mouse model of ALS (SOD1G93A-transgenic mice), and (3) a group of 31 patients with sporadic ALS. We found that melatonin attenuates glutamate-induced cell death of cultured motoneurons. In SOD1G93A-transgenic mice, high-dose oral melatonin delayed disease progression and extended survival. In a clinical safety study, chronic high-dose (300 mg/day) rectal melatonin was well tolerated during an observation period of up to 2 yr. Importantly, circulating serum protein carbonyls, which provide a surrogate marker for oxidative stress, were elevated in ALS patients, but were normalized to control values by melatonin treatment. This combination of preclinical effectiveness and proven safety in humans suggests that high-dose melatonin is suitable for clinical trials aimed at neuroprotection through antioxidation in ALS.

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