Tuesday, 19 August 2014

Saving oligodendrocytes

Vakilzadeh G, Khodagholi F, Ghadiri T, Darvishi M, Ghaemi A, Noorbakhsh F, Gorji A, Sharifzadeh M. Protective Effect of a cAMP Analogue on Behavioral Deficits and Neuropathological Changes in Cuprizone Model of Demyelination. Mol Neurobiol. 2014 Aug. [Epub ahead of print]

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, inflammation, and apoptotic (cell suicide) , as well as anti-apoptotic factors in cuprizone model of demyelination. C57BL/6J mice were fed with chow containing 0.2 % cuprizone (a chemical that kills oligodendrocytes in certain areas of the brain) 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.


Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3'-5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is derived from adenosine triphosphate (ATP) and used for intracellular signal transduction in many different organisms, conveying the cAMP-dependent pathway.Bucladesine is a cyclic nucleotide derivative which mimics the action of endogenous cAMP and is a phosphodiesterase inhibitor

Bucladesine is a cell permeable cAMP analog. The compound is used in a wide variety of research applications because it mimics cAMP and can induce normal physiological responses when added to cells in experimental conditions. cAMP is only able to elicit minimal responses in these situations.
In this study it protects against chemical induced demyelination and was associated with lack of up regulation of interleukin 6 a pro-inflammatory cytokine that can activate astrocytes and NF-kappaB is a protein complex that controls transcription of DNA. NF-κB plays a key role in regulating the immune response and is a protein responsible for cytokine production and cell survival. This was associated with more Bcl-2 (B-cell lymphoma 2) is a member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inducing (pro-apoptotic) it or inhibiting it (anti-apoptotic). Bcl-2 is specifically considered as an important anti-apoptotic (slops cell death) protein. This was associated with less BAX,or Apoptosis regulator BAX also known as bcl-2-like protein 4 supports cell suicide and is pro apototic this is involved in stimulation of the cell death effector cascade of which Caspase 3 is an executioner in cells . So less oligodendrocytes are killed in this experiment. 

Is this pathway useful in humans we will have to wait and see. This activity seems to be slowing oligodendrocyte loss rather than promoting repair



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