Reduced oxidative damage in ALS by high-dose enteral melatonin treatment.
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.
Weishaupt
Jochen H
JH
Department of Neurology, Georg August University, Göttingen, Germany.
Bartels
Claudia
C
Pölking
Esther
E
Dietrich
Jeannine
J
Rohde
Gundula
G
Poeggeler
Burkhard
B
Mertens
Nina
N
Sperling
Swetlana
S
Bohn
Matthias
M
Hüther
Gerald
G
Schneider
Armin
A
Bach
Alfred
A
Sirén
Anna-Leena
AL
Hardeland
Rüdiger
R
Bähr
Mathias
M
Nave
Klaus-Armin
KA
Ehrenreich
Hannelore
H
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
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