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.

Effects of TRPV1 on the hippocampal synaptic plasticity in the epileptic rat brain

“…The developed films were scanned densitometrically on Bio‐Rad scanner. Quantitative analysis was carried out by the monomeric bands data with Image J software (Vakilzadeh et al, ).…”

Roflumilast, a cAMP-Specific Phosphodiesterase-4 Inhibitor, Reduces Oxidative Stress and Improves Synapse Functions in Human Cortical Neurons Exposed to the Excitotoxin Quinolinic Acid

“…Phosphodiesterases (PDEs) are a class of enzymes that inactivate the essential second messengers cyclic 3′-5′ adenosine monophosphate (cAMP) and cyclic 3′-5′ guanosine monophosphate (cGMP), which are involved in various intracellular signaling pathways. , Impaired cAMP and cGMP signaling is implicated in several neurological disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), multiple sclerosis (MS), schizophrenia, and depression . The phosphodiesterase 4 (PDE4) family includes cAMP-specific enzymes that are expressed in the cortical, hippocampus, and striatum regions in the rat brain. − The overexpression of PDE4 is shown to deplete cAMP levels in the mice brain .…”

Thalamocortical-auditory network alterations following cuprizone‐induced demyelination

“…Cuprizone-induced demyelination is usually followed by complete remyelination within a few weeks. Thus, cuprizone treatment serves a useful animal model for investigation of the processes involved in demyelination and consequent remyelination [ 21 – 23 ]. To study how demyelination may affect neuronal function and synaptic transmission of the thalamocortical system, we used the cuprizone-mediated demyelination/remyelination model to investigate single cortical neuron properties as well as synaptic plasticity under demyelinated and remyelinated conditions in the auditory cortex in vitro.…”