The selective inhibition of phosphodiesterase 4 (PDE4), reduces neuroinflammation and promotes the regeneration of myelin, according to a study published in the journal Brain, Behavior, and Immunity. Since neuroinflammation and demyelination are critical events during the pathogenesis of multiple sclerosis (MS), selective PDE4 inhibition could be a potential avenue in the treatment of the disease.

During the study, a team of researchers led by Tim Vanmierlo, PhD, used in vitro, ex vivo, and in vivo models to elucidate the function of the different subtypes of PDE4 in reducing inflammation and promoting myelin repair.

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The team showed that PDE4D was specifically involved in promoting myelination while PDE4B had antiinflammatory effects. 

When they inhibited PDE4D in oligodendrocyte progenitor cells from mice or derived from human induced pluripotent stem cells, the researchers found that the differentiation of these cells was increased and remyelination was enhanced. Moreover, PDE4D inhibition promoted remyelination in a mouse model of MS and improved spatial memory and reduced visual evoked potential latency times.

On the other hand, when they specifically inhibited PDE4B, the researchers found that the production of nitric oxide was reduced in vitro suggesting an anti-inflammatory effect. Moreover, PDE4B inhibition improved neurological scores during the early phase of experimental autoimmune encephalomyelitis in vivo.  

Importantly, the agents used to specifically inhibit PDE4D and PDE4B did not cause side effects such as nausea and vomiting like when full PDE4 inhibitors are used.

Finally, the researchers showed that the neurons in the area postrema in the brainstem in humans and in cells from the oligodendroglia lineage had distinct PDE4D isoform expression patterns and that the pde4d1/2 and pde4d6 genes were the key targets that could induce the differentiation of oligodendrocyte progenitor cells.

“Collectively, these data demonstrate that gene specific PDE4 inhibitors have potential as novel therapeutic agents for targeting the distinct disease processes of MS,” the researchers wrote. 

PDE4 is the major enzyme class responsible for the hydrolysis of cyclic adenosine monophosphate, which is involved in controlling inflammation. The enzyme consists of 4 subtypes (PDE4A to PDE4D), which are each coded by different genes. PDE4 inhibition has been proposed as a potential treatment for a number of neurological conditions.

Reference

Schepers M, Paes D, Tiane A, et al. Selective PDE4 subtype inhibition provides new opportunities to intervene in neuroinflammatory versus myelin damaging hallmarks of multiple sclerosis. Brain Behav Immun. Published online December 28, 2022. doi:10.1016/j.bbi.2022.12.020