title: Reduced oxidative damage in ALS by high-dose enteral melatonin treatment.
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 (SOD1(G93A)-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 SOD1(G93A)-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.
authors.affiliation: Department of Neurology, Georg August University, Göttingen, Germany.
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Weishaupt
authors.forename: Claudia
authors.initials: C
authors.lastname: Bartels
authors.forename: Esther
authors.initials: E
authors.lastname: Pölking
authors.forename: Jeannine
authors.initials: J
authors.lastname: Dietrich
authors.forename: Gundula
authors.initials: G
authors.lastname: Rohde
authors.forename: Burkhard
authors.initials: B
authors.lastname: Poeggeler
authors.forename: Nina
authors.initials: N
authors.lastname: Mertens
authors.forename: Swetlana
authors.initials: S
authors.lastname: Sperling
authors.forename: Matthias
authors.initials: M
authors.lastname: Bohn
authors.forename: Gerald
authors.initials: G
authors.lastname: Hüther
authors.forename: Armin
authors.initials: A
authors.lastname: Schneider
authors.forename: Alfred
authors.initials: A
authors.lastname: Bach
authors.forename: Anna-Leena
authors.initials: AL
authors.lastname: Sirén
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Hardeland
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.forename: Hannelore
authors.initials: H
authors.lastname: Ehrenreich
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015415:Biomarkers; D002460:Cell Line; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D018698:Glutamic Acid / Q000633:toxicity; D006801:Humans; D008297:Male; D008550:Melatonin / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D015996:Survival Rate; D014810:Vitamin E / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; D014810:Vitamin E; D018698:Glutamic Acid; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D008550:Melatonin