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Protective Effect of a cAMP Analogue on Behavioral Deficits and Neuropathological Changes in Cuprizone Model of Demyelination.

Molecular neurobiology (2014-08-17)
Gelareh Vakilzadeh, Fariba Khodagholi, Tahereh Ghadiri, Marzieh Darvishi, Amir Ghaemi, Farshid Noorbakhsh, Ali Gorji, Mohammad Sharifzadeh
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Pyridoxal 5′-phosphate hydrate, ≥98%
Sigma-Aldrich
Pyridoxal 5′-phosphate monohydrate, ≥97.0% (NT)
Sigma-Aldrich
Pyridoxal 5′-phosphate hydrate, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Xylazine, ≥99%
Sigma-Aldrich
Adenosine 3′,5′-cyclic monophosphate tris salt, ≥97% (HPLC), powder