Abstract
Multiple Sclerosis (MS) is a neurodegenerative disease where immune-driven demyelination occurs with inefficient remyelination, but therapies are limited, especially those to enhance repair. Here, we show that the dual phosphodiesterase (PDE)7- glycogen synthase kinase (GSK)3 inhibitor, VP3.15, a heterocyclic small molecule with good pharmacokinetic properties and safety profile, improves in vivo remyelination in mouse and increases both adult mouse and adult human oligodendrocyte progenitor cell (OPC) differentiation, in addition to its immune regulatory action. The dual inhibition is synergistic, as increasing intracellular levels of cAMP by cyclic nucleotide PDE inhibition both suppresses the immune response and increases remyelination, and in addition, inhibition of GSK3 limits experimental autoimmune encephalomyelitis in mice. This combination of an advantageous effect on the immune response and an enhancement of repair, plus demonstration of its activity on adult human OPCs, leads us to propose dual PDE7-GSK3 inhibition, and specifically VP3.15, as a neuroprotective and neuroreparative disease-modifying treatment for MS.
Highlights
In this context, we have recently shown the anti-inflammatory and neuroprotective effects of the cAMP-specific phosphodiesterase 7 (PDE7) inhibitors in animal models of spinal cord injury, stroke, Parkinsons and Alzheimers diseases, and MS29–38
VP3.15 had no additional effect on morphology of mature oligodendrocytes as the number of processes and subprocesses was not different to control
We show that dual PDE7-glycogen synthase kinase 3 (GSK3) inhibition aids Central Nervous System (CNS) remyelination in a variety of ex vivo and in vivo demyelination models, by enhancing differentiation of oligodendrocyte progenitor cells (OPCs)
Summary
We have recently shown the anti-inflammatory and neuroprotective effects of the cAMP-specific phosphodiesterase 7 (PDE7) inhibitors in animal models of spinal cord injury, stroke, Parkinsons and Alzheimers diseases, and MS29–38. Their effect on remyelination remains unknown, previous data from our group have shown that PDE7 inhibitors favour the differentiation and survival of mouse cortical OPCs and the differentiation of adult human OPCs in vitro[39]. PDE7 inhibition leads to an enhancement of the intracellular levels of cAMP without intolerable gastrointestinal side effects[40], making them potential and attractive therapeutic agents. Our results lead us to propose these dual PDE7-GSK3 inhibitors, especially VP3.15 with its good oral bioavailability and CNS penetration, as potential combined anti-inflammatory and pro-remyelinating therapies for MS
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