4 research outputs found
Inhibition of phosphodiesterase-4 promotes oligodendrocyte precursor cell differentiation and enhances CNS remyelination
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
Inhibition of phosphodiesterase‐4 promotes oligodendrocyte precursor cell differentiation and enhances CNS
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