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

Abstract

Background and Purpose PDE4 inhibition suppresses experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, side effects hinder PDE4 inhibitors clinical use. PDE7 inhibition might constitute an alternative therapeutic strategy, but few data about the anti‐inflammatory potential of PDE7 inhibitors are currently available. We have used the EAE model to perform a comparative evaluation of PDE4 and PDE7 inhibition as strategies for MS treatment. Experimental Approach Two PDE7 inhibitors, the sulfonamide derivative BRL50481 and the recently described quinazoline compound TC3.6, were assayed to modulate EAE in SJL mice, in comparison with the well‐known PDE4 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 TC3.6 prevented EAE with efficacy similar to Rolipram, while BRL50481 had no effect on the disease. Differences between both PDE7 inhibitors are discussed. Data from Rolipram and TC3.6 showed that PDE4 and PDE7 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 TC3.6 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 Foxp3. Conclusions and Implications These results provide new information about the effects of Rolipram on EAE, underline PDE7 inhibition as a new therapeutic target for inflammatory diseases and show the value of TC3.6 to prevent EAE, with possible consequences for new therapeutic tools in MS.

Roflumilast Reduces Cerebral Inflammation in a Rat Model of Experimental Subarachnoid Hemorrhage

“…It is expressed in the cortex and hippocampus. Inhibition of PDE-4 yields beneficial effects in animal models of neurological diseases and injuries where inflammation plays an essential role, such as spinal cord injury [9], traumatic brain injury [10], Alzheimer’s disease [11], major depressive disorder [12], multiple sclerosis [13], and ischemic stroke [14, 15]. Roflumilast, a highly selective PDE-4 inhibitor, has been approved by the Food and Drug Administration (FDA) of USA as an anti-inflammation drug for peripheral inflammatory disorders, severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis [16, 17].…”

Propentofylline, phosphodiesterase and adenosine reuptake inhibitor modulates lymphocyte subsets and lymphocyte activity after in-vivo administration in non-immunized and SRBC-immunized mice

“…Regulatory T cells are crucial for maintaining the balance of immune response and play a potential role in the treatment of autoimmunity disorders, allergy and preventing transplant rejection …”

“…Regulatory T cells are crucial for maintaining the balance of immune response and play a potential role in the treatment of autoimmunity disorders, allergy and preventing transplant rejection. [24][25][26][27] Selective PDE3 inhibitors (cilostamide, cilostazol) were found to increase Foxp3 + T-cell population and augment their suppressive activity towards T cells both in vitro and in vivo. [25,28] Kim et al [29] investigated the impact of roflumilast (selective PDE4 inhibitor) on lung chronic graft-versus-host disease in mice and demonstrated downregulation of pro-inflammatory cytokines (IL-1b and IL-6) and an increase in the percentage of Foxp3 + T regulatory cells.…”

“…[25,28] Kim et al [29] investigated the impact of roflumilast (selective PDE4 inhibitor) on lung chronic graft-versus-host disease in mice and demonstrated downregulation of pro-inflammatory cytokines (IL-1b and IL-6) and an increase in the percentage of Foxp3 + T regulatory cells. Gonz alez-Garc ıa et al [26] examined mice with experimental autoimmune encephalomyelitis (EAE) and reported that rolipram (selective PDE4 inhibitor) and TC3.6 (selective PDE7 inhibitor) increased the expression of Foxp3 mRNA. Similarly, in the present study propentofylline caused an increase in the population of Treg (CD4 + CD25 + Foxp3 + ) cells.…”

PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis

“…In immune cells, inhibition of PDE4 limits the production and release of pro‐inflammatory cytokines from activated peripheral mononuclear cells, including but not limited to, TNF‐α, IL‐2, IL‐12 and IFN‐γ (Kaminuma et al ., ; Muise et al ., ; Claveau et al ., ). In addition, the prototypical PDE4 inhibitor, rolipram, has been demonstrated to be a potent anti‐inflammatory agent in the EAE model of MS (Sommer et al ., ; Sanchez et al ., ; Paintlia et al ., ; Gonzalez‐Garcia et al ., ) but its secondary emetic effects in humans have hindered its clinical development (Robichaud et al ., ). An alternative approach is to inhibit other cAMP‐specific PDE isoenzymes expressed in immune and neural cells such as PDE7 (Lee et al ., ).…”