Comparative assessment of PDE 4 and 7 inhibitors as therapeutic agents in experimental autoimmune encephalomyelitis

Background and Purpose PDE 4 inhibition suppresses experimental autoimmune encephalomyelitis ( EAE ), an animal model of multiple sclerosis ( MS ). However, side effects hinder PDE 4 inhibitors clinical use. PDE 7 inhibition might constitute an alternative therapeutic strategy, but few data about the anti‐inflammatory potential of PDE 7 inhibitors are currently available. We have used the EAE model to perform a comparative evaluation of PDE 4 and PDE 7 inhibition as strategies for MS treatment. Experimental Approach Two PDE 7 inhibitors, the sulfonamide derivative BRL 50481 and the recently described quinazoline compound TC 3.6, were assayed to modulate EAE in SJL mice, in comparison with the well‐known PDE 4 inhibitor Rolipram. We evaluated clinical signs, presence of inflammatory infiltrates in CNS and anti‐inflammatory markers. We also analysed the effect of these inhibitors on the inflammatory profile of spleen cells in vitro . Key Results TC 3.6 prevented EAE with efficacy similar to Rolipram, while BRL 50481 had no effect on the disease. Differences between both PDE 7 inhibitors are discussed. Data from Rolipram and TC 3.6 showed that PDE 4 and PDE 7 inhibition work through both common and distinct pathways. Rolipram administration caused an increase in IL ‐10 and IL ‐27 expression which was not found after TC 3.6 treatment. On the other hand, both inhibitors reduced IL ‐17 levels, prevented infiltration in CNS and increased the expression of the T regulator cell marker F oxp3. Conclusions and Implications These results provide new information about the effects of Rolipram on EAE , underline PDE 7 inhibition as a new therapeutic target for inflammatory diseases and show the value of TC 3.6 to prevent EAE , with possible consequences for new therapeutic tools in MS .