Treatment with the dual PDE7-GSK3 inhibitor VP3.15 may be a successful integrative therapeutic strategy for treating primary progressive multiple sclerosis, an aggressive form of multiple sclerosis, according to a study in the International Journal of Molecular Sciences.

Prior studies have suggested that VP3.15 is the most promising dual inhibitor compound because of its neuroprotective and immunomodulatory function, noted Rocio Benítez-Fernández, of the Centro de Investigaciones Biológicas Margarita Salas-CSIC in Madrid, Spain, and colleagues noted.

The research team evaluated the therapeutic potential of the VP3.15 dual inhibitor on the Theiler’s virus model. It assessed several factors, including neurological deficits, leukocyte infiltration, axonal damage, and proinflammatory mediators.

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The study reported that VP3.15 treatments for 15 days in the model resulted in microglial activation and infiltration of CD4+ T lymphocytes and made it possible to recover nearly all the motor deficits found in Theiler’s mouse encephalomyelitis virus (TMEV) mice.

The findings suggested that treatment with VP3.15 in the Theiler’s mouse encephalomyelitis virus-induced demyelinated disease (TMEV-IDD) model animates the differentiation toward myelinating phenotypes, even though the TMEV-IDD model does not create a proliferation of oligodendrocyte progenitor cells. These results remained consistent with the previous results.

“Thus, in this study, we proposed for the first time the dual inhibition of GSK3β and PDE7 as a therapy for PPMS by analyzing the neuroprotective, anti-inflammatory, and neurorepairing activity of VP3.15. The compound was evaluated only after symptoms appeared to mimic the time when treatment was started in MS patients”, the authors concluded.

The research team proposed 2 ways to investigate the anti-inflammatory role of the VP3.15 dual inhibitor, The first was to inhibit PDE7 by considering the increased levels of cAMP, which significantly limited the inflammatory response both by decreasing the lymphocyte infiltration and microglial activation. The second way was the modulation of the NF-κB pathway by inhibiting GSK3β, which reduced the inflammatory response.

They found that treatment with this inhibitor resulted in microglial activation and infiltration of CD4+ T lymphocytes, thereby favoring a neuroprotective process, possibly through a reduction in chronic demyelination and promotion of myelin repair mechanisms.

“On the whole, the results of the present study allow us to affirm that treatment with a dual inhibitor of GSK3β and PDE7 in a “primary-progressive” preclinic MS model is capable of modulating the inflammatory response, influencing neuroprotective mechanisms and promoting the differentiation of oligodendrocyte progenitor cells, to achieve greater preservation of myelin and axonal integrity,” the authors concluded.


Benítez-Fernández R, Gil C, Guaza C, et al. The dual PDE7-GSK3β inhibitor, VP3.15, is a neuroprotective disease-modifying treatment in a primary progressive multiple sclerosis model. Int J Mol Sci. Published online November 19, 2022. doi: 10.3390/ijms232214378.