title: Intraperitoneal melatonin is not neuroprotective in the G93ASOD1 transgenic mouse model of familial ALS and may exacerbate neurodegeneration.
abstract: In amyotrophic lateral sclerosis (ALS) reactive oxygen species and apoptosis are implicated in disease pathogenesis. Melatonin with its anti-oxidant and anti-apoptotic properties is expected to ameliorate disease phenotype. The aim of this study was to assess possible neuroprotection of melatonin in the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. Four groups of mice, 14 animals each, were injected intraperitoneally with 0mg/kg, 0.5mg/kg, 2.5mg/kg and 50mg/kg of melatonin from age 40 days. The primary end points were; disease onset, disease duration, survival and rotarod performance. No statistically significant difference in disease onset between the four groups was found. Survival was significantly reduced with the 0.5mg/kg and 50mg/kg doses and tended to be reduced with the 2.5mg/kg dose. Histological analysis of spinal cords revealed increased motoneuron loss in melatonin treated mice. Melatonin treated animals were associated with increased oxidative stress as assessed with 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation. Histochemistry and Western blot data of spinal cord from melatonin treated mice revealed upregulation of human SOD1 compared to untreated mice. In addition, real-time PCR revealed a dose dependent upregulation of human SOD1 in melatonin treated animals. Thus, intraperitoneal melatonin, at the doses used, does not ameliorate and perhaps exacerbates phenotype in the G93ASOD1 mouse ALS model. This is probably due to melatonin's effect on upregulating gene expression of human toxic SOD1. This action presumably overrides any of its direct anti-oxidant and anti-apoptotic properties.
authors.affiliation: The Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus.
authors.forename: Efthimios
authors.initials: E
authors.lastname: Dardiotis
authors.forename: Elena
authors.initials: E
authors.lastname: Panayiotou
authors.forename: Marianne L
authors.initials: ML
authors.lastname: Feldman
authors.forename: Andreas
authors.initials: A
authors.lastname: Hadjisavvas
authors.forename: Stavros
authors.initials: S
authors.lastname: Malas
authors.forename: Ilia
authors.initials: I
authors.lastname: Vonta
authors.forename: Georgios
authors.initials: G
authors.lastname: Hadjigeorgiou
authors.forename: Kyriakos
authors.initials: K
authors.lastname: Kyriakou
authors.forename: Theodoros
authors.initials: T
authors.lastname: Kyriakides
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000009:adverse effects; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D007263:Infusions, Parenteral; D008550:Melatonin / Q000008:administration & dosage* / Q000009:adverse effects*; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000008:administration & dosage; D018384:Oxidative Stress / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000975:Antioxidants; D002492:Central Nervous System Depressants; D018696:Neuroprotective Agents; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D008550:Melatonin
keywords: ALS; Amyotrophic lateral sclerosis; G93ASOD1 transgenic mouse model; Melatonin; Neuroprotection; Oxidative stress; SOD1; amyotrophic lateral sclerosis; superoxide dismutase gene