Treatment of Experimental Autoimmune Encephalomyelitis with an Inhibitor of Phosphodiesterase-8 (PDE8)

Abstract

After decades of development, inhibitors targeting cyclic nucleotide phosphodiesterases (PDEs) expressed in leukocytes have entered clinical practice for the treatment of inflammatory disorders, with three PDE4 inhibitors being in clinical use as therapeutics for psoriasis, psoriatic arthritis, chronic obstructive pulmonary disease and atopic dermatitis. In contrast, the PDE8 family that is upregulated in pro-inflammatory T cells is a largely unexplored therapeutic target. We have previously demonstrated a role for the PDE8A-Raf-1 kinase complex in the regulation of myelin oligodendrocyte glycoprotein peptide 35–55 (MOG35–55) activated CD4+ effector T cell adhesion and locomotion by a mechanism that differs from PDE4 activity. In this study, we explored the in vivo treatment of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS) induced in mice immunized with MOG using the PDE8-selective inhibitor PF-04957325. For treatment in vivo, mice with EAE were either subcutaneously (s.c.) injected three times daily (10 mg/kg/dose), or were implanted subcutaneously with Alzet mini-osmotic pumps to deliver the PDE8 inhibitor (15.5 mg/kg/day). The mice were scored daily for clinical signs of paresis and paralysis which were characteristic of EAE. We observed the suppression of the clinical signs of EAE and a reduction of inflammatory lesion formation in the CNS by histopathological analysis through the determination of the numbers of mononuclear cells isolated from the spinal cord of mice with EAE. The PDE8 inhibitor treatment reduces the accumulation of both encephalitogenic Th1 and Th17 T cells in the CNS. Our study demonstrates the efficacy of targeting PDE8 as a treatment of autoimmune inflammation in vivo by reducing the inflammatory lesion load.

Selective PDE4 subtype inhibition provides new opportunities to intervene in neuroinflammatory versus myelin damaging hallmarks of multiple sclerosis

“…The indirect effect of rolipram on IL-17 production is thought to be mediated by monocytes' elevated production of IL-27 (Gonzalez-Garcia et al, 2013;Batten et al, 2006;Stumhofer et al, 2006). Previously, it has also been shown that the expression of the cAMP-specific PDE8A is induced in activated T lymphocytes, and inhibition of the complete PDE8 family by PF-04957325 (10 mg/kg) has been shown to suppress neuroinflammation, thereby reducing the inflammatory lesion load in the EAE animal model (Basole et al, 2022;Glavas et al, 2001). The therapeutic potential of the cAMP-specific PDE4, PDE7 and PDE8 inhibitors highlights the crucial role of cAMP in modulating the anti-inflammatory responses.…”

Regulation of intracellular cAMP levels in osteocytes by mechano-sensitive focal adhesion kinase via PDE8A

“…We next turned our attention to phosphodiesterase 8A (PDE8A), a selective cAMP phosphodiesterase [32] that was also identified as a possible FAK substrate in our phosphoproteomic study at position Y315 ( Figure 1d ). GloSensor Saos2 cells were treated with the selective PDE8A inhibitor PF04957325 [33] ± isoproterenol or PTH. Both basal and ligand-stimulated cAMP levels were increased by PDE8A inhibitor treatment ( Figure 6a ).…”

A mini-review: phosphodiesterases in charge to balance intracellular cAMP during T-cell activation

“…The research conducted over the years focusing on the role of PDE8 on T-cell function was reviewed more in detail recently (45). Notably, the PDE8 inhibitor PF-04957325 is able to reduce the inflammatory lesion formation in the central nervous system in the experimental autoimmune encephalomyelitis (EAE) mouse model for multiple sclerosis (46). Table 1 summarizes previous findings about PDE expression and regulation during T cell activation.…”