Syed YA, Baer A, Hofer MP, González GA, Rundle J, Myrta S, Huang JK, Zhao C, Rossner MJ, Trotter MW, Lubec G, Franklin RJ, Kotter MR. Inhibition of phosphodiesterase-4 promotes oligodendrocyte precursor cell differentiation and enhances CNS remyelination. EMBO Mol Med. 2013 Dec;5(12):1918-34. doi: 10.1002/emmm.201303123. Epub 2013 Oct 21.
The increasing effectiveness of new disease-modifying drugs that suppress disease activity in multiple sclerosis has opened up opportunities for regenerative medicines that enhance remyelination and potentially slow disease progression. Although several new targets for therapeutic enhancement of remyelination have emerged, few lend themselves readily to conventional drug development. Here, we used transcription profiling to identify mitogen-activated protein kinase (Mapk) signalling as an important regulator involved in the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes. We show in tissue culture that activation of Mapk signalling by elevation of intracellular levels of cyclic adenosine monophosphate (cAMP) using administration of either dibutyryl-cAMP or inhibitors of the cAMP-hydrolysing enzyme phosphodiesterase-4 (Pde4) enhances OPC differentiation. Finally, we demonstrate that systemic delivery of a PDE4-inhibitor leads to enhanced differentiation of OPCs within focal areas of toxin-induced demyelination and a consequent acceleration of remyelination. These data reveal a novel approach to therapeutic enhancement of remyelination amenable to pharmacological intervention and hence with significant potential for translation.
In recent months a whole host of new remyelinating actors have been described. This study finds inhibition of PDE-4 as a promising route. PDE4 inhibition has been tried in MS and there are at least two planned trials in the very near future using idubilast, which is a PDE-4 inhibitor. However there is also data with rolipram another PDE-4 inhibitor. This blocked tumor necrosis factor and inhibited the development of EAE. However blockade of TNF in MS makes disease worse and a trial in MS with rolipram was stopped because of disease worsening. Likewise in EAE it made symptoms worse. Therefore when aiming to treat disease with agents that block ubiquitous targets, side-effects are the name of the game. In many biological processes the specificity is at the surface of the cell and the receptors they express. These then signal via common signalling molecules and therefore blockade can have lots of unwanted effects.