title: Protective effects of melatonin against mitochondrial injury in a mouse model of multiple sclerosis.
abstract: Multiple sclerosis (MS) is the most prevalent inflammatory demyelinating disease of the central nervous system. Besides other pathophysiological mechanisms, mitochondrial injury is crucially involved in the development and progression of this disease. Mitochondria have been identified as targets for the peptide hormone melatonin. In the present study, we sought to evaluate the impact of oxidative stress on mitochondrial density and enzyme transcription during experimentally induced demyelination and the protective influence of melatonin. Adult male mice were fed with cuprizone for 5 weeks which caused severe demyelination of the corpus callosum (CC). Animals were simultaneously treated with melatonin by daily intra-peritoneal injections. Melatonin exposure reversed cuprizone-induced demyelination and axon protection. Transmission electron microscopy demonstrated significantly increased mitochondrial numbers and slightly increased mitochondrial size within CC axons after cuprizone exposure. Melatonin antagonized these effects and, in addition, induced the expression of subunits of the respiratory chain complex over normal control values reflecting a mechanism to compensate cuprizone-mediated down-regulation of these genes. Similarly, melatonin modulated gene expression of mitochondrial fusion and fission proteins. Biochemical analysis showed that oxidative stress induced by cuprizone was regulated by melatonin. The data implicate that melatonin abolishes destructive cuprizone effects in the CC by decreasing oxidative stress, restoring mitochondrial respiratory enzyme activity and fusion and fission processes as well as decreasing intra-axonal mitochondria accumulation.
authors.affiliation: Department of Anatomical Sciences, School of Medicine, Tehran University of Medical Sciences, 16 Azar Street, Poursina Street, Tehran, Iran, ragerdi@sina.tums.ac.ir.
authors.forename: Iraj Ragerdi
authors.initials: IR
authors.lastname: Kashani
authors.forename: Zahra
authors.initials: Z
authors.lastname: Rajabi
authors.forename: Mohammad
authors.initials: M
authors.lastname: Akbari
authors.forename: Gholamreza
authors.initials: G
authors.lastname: Hassanzadeh
authors.forename: Alireza
authors.initials: A
authors.lastname: Mohseni
authors.forename: Mohammadtaha Kouchakinejad
authors.initials: MK
authors.lastname: Eramsadati
authors.forename: Kheirollah
authors.initials: K
authors.lastname: Rafiee
authors.forename: Cordian
authors.initials: C
authors.lastname: Beyer
authors.forename: Markus
authors.initials: M
authors.lastname: Kipp
authors.forename: Adib
authors.initials: A
authors.lastname: Zendedel
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D003471:Cuprizone / Q000633:toxicity; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008550:Melatonin / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000633:toxicity; D009103:Multiple Sclerosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D008996:Monoamine Oxidase Inhibitors; D018991:Myelin Proteolipid Protein; D003471:Cuprizone; D010088:Oxidoreductases; C432586:ubiquinol oxidase; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D025261:Mitochondrial Proton-Translocating ATPases; C501006:mt-Atp6 protein, mouse; D005978:Glutathione; D008550:Melatonin