title: Protective Effect of a cAMP Analogue on Behavioral Deficits and Neuropathological Changes in Cuprizone Model of Demyelination.
abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease that leads to neuronal cell loss. Cyclic AMP and its analogs are well known to decrease inflammation and apoptosis. In the present study, we examined the effects of bucladesine, a cell-permeable analogue of cyclic adenosine monophosphate (cAMP), on myelin proteins (PLP, PMP-22), inflammation, and apoptotic, as well as anti-apoptotic factors in cuprizone model of demyelination. C57BL/6J mice were fed with chow containing 0.2% copper chelator cuprizone or vehicle by daily oral gavage for 5 weeks to induce reversible demyelination predominantly of the corpus callosum. Bucladesine was administered intraperitoneally at different doses (0.24, 0.48, or 0.7 μg/kg body weight) during the last 7 days of 5-week cuprizone treatment. Bucladesine exhibited a protective effect on myelination. Furthermore, bucladesine significantly decreased the production of interleukin-6 pro-inflammatory mediator as well as nuclear factor-κB activation and reduced the mean number of apoptotic cells compared to cuprizone-treated mice. Bucladesine also decreased production of caspase-3 as well as Bax and increased Bcl-2 levels. Our data revealed that enhancement of intracellular cAMP prevents demyelination and plays anti-inflammatory and anti-apoptotic properties in mice cuprizone model of demyelination. This suggests the modulation of intracellular cAMP as a potential target for treatment of MS.
authors.affiliation: School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Gelareh
authors.initials: G
authors.lastname: Vakilzadeh
authors.forename: Fariba
authors.initials: F
authors.lastname: Khodagholi
authors.forename: Tahereh
authors.initials: T
authors.lastname: Ghadiri
authors.forename: Marzieh
authors.initials: M
authors.lastname: Darvishi
authors.forename: Amir
authors.initials: A
authors.lastname: Ghaemi
authors.forename: Farshid
authors.initials: F
authors.lastname: Noorbakhsh
authors.forename: Ali
authors.initials: A
authors.lastname: Gorji
authors.forename: Mohammad
authors.initials: M
authors.lastname: Sharifzadeh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D003994:Bucladesine / Q000008:administration & dosage / Q000494:pharmacology; D003471:Cuprizone; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003711:Demyelinating Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007274:Injections, Intraperitoneal; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009068:Movement; D009186:Myelin Sheath / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D059225:Nociception / Q000187:drug effects
chemical_list: D015415:Biomarkers; D015850:Interleukin-6; D016328:NF-kappa B; D018696:Neuroprotective Agents; D003471:Cuprizone; D003994:Bucladesine; D000242:Cyclic AMP; D051547:Heme Oxygenase-1