Saturday, 11 August 2012

Research: Promoting remyelination is not a simple task


OBJECTIVE: Rolipram, a 3'-5'-cyclic adenosine monophosphate (cAMP)-dependent phosphodiesterase 4 (PDE4) inhibitor, has long been studied for its immune modulating effects in the treatment of experimental autoimmune encephalomyelitis (EAE). In the current study, we investigated the effects of rolipram on remyelination after cuprizone- or lysolecithin-induced demyelination and the signal transduction pathways potentially modulating this response.
 
MATERIALS AND METHODS: Cuprizone-induced demyelination in mice and lysolecithin (LPC)-induced demyelination in rat cerebellum slice culture were treated with rolipram. Demyelination was evaluated by Luxol fast blue (LFB) or myelin basic protein (MBP) staining and western blot. Oligodendroglial cells were cultured with different concentrations of rolipram, and 2', 3'-cyclic nucleotide phosphodiesterase (CNPase) activity, MBP expression, and extracellular signal-regulated kinase (ERK) phosphorylation were measured.
 
RESULTS: Rolipram antagonized lysolecithin (LPC)-induced demyelination in rat cerebellar slice cultures and cuprizone-fed mice. In vitro, rolipram treatment promoted oligodendrocyte precursor cell (OPC) maturation, an effect that was partially blocked by the inhibitors of the mitogen activated protein kinase kinase (MEK).
 
CONCLUSION: Rolipram promotes the maturation of OPCs, facilitates remyelination, and increases ERK phosphorylation. All of these actions are involved in an action against cuprizone-induced demyelination that may occur partly via the MEK-ERK pathway. Importantly, this may have therapeutic implications for MS.
                                          Image of rolipram binding to brain. It goes everywhere

This study suggests that a drug called rolipram can promote the development of remyelination through stimulation of oligodendrocytes. This sounds great but this is a dead duck approach. Why? Well this because rolipram does other things such as inhibit tumor necrosis factor and makes MS worse. So whilst it may have remyelination potential because the pathways targeted are used by many cell types it has unwanted effects and this prevents you from using this. This is not going to be an uncommon situation. The RXR retinoid receptor has been another molecule that has been found to be pro-remyelination. However again this is a ubiqitious receptor throughout the body and so long-term stimulation may be anticipated to come with all sorts of side-effects. This is the problem with translating basic science becuase within the microcosm of your little science view things may be active in the clinic you have to see the big picture and realise that there may be alternative actions.

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