Inhibition of phosphodiesterase-4 promotes oligodendrocyte precursor cell differentiation and enhances CNS remyelination

The increasing effectiveness of new disease-modifying drugs that suppress\ud disease activity in multiple sclerosis has opened up opportunities for\ud regenerative medicines that enhance remyelination and potentially slow disease\ud progression. Although several new targets for therapeutic enhancement of\ud remyelination have emerged, few lend themselves readily to conventional drug\ud development. Here, we used transcription profiling to identify mitogen-activated\ud protein kinase (Mapk) signalling as an important regulator involved in the\ud differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes.\ud We show in tissue culture that activation of Mapk signalling by elevation of\ud intracellular levels of cyclic adenosine monophosphate (cAMP) using administration\ud of either dibutyryl-cAMP or inhibitors of the cAMP-hydrolysing enzyme\ud phosphodiesterase-4 (Pde4) enhances OPC differentiation. Finally, we demonstrate\ud that systemic delivery of a Pde4 inhibitor leads to enhanced differentiation\ud of OPCs within focal areas of toxin-induced demyelination and a consequent\ud acceleration of remyelination. These data reveal a novel approach to therapeutic\ud enhancement of remyelination amenable to pharmacological intervention and\ud hence with significant potential for translation.