PDE4 Inhibition and Inflammatory Bowel Disease: A Novel Therapeutic Avenue

Abstract

Background. In the last few decades, a better knowledge of the inflammatory pathways involved in the pathogenesis of Inflammatory Bowel Disease (IBD) has promoted biological therapy as an important tool to treat IBD patients. However, in spite of a wider spectrum of biological drugs, a significant proportion of patients is unaffected by or lose their response to these compounds, along with increased risks of infections and malignancies. For these reasons there is an urgent need to look for new pharmacological targets. The novel Phosphodiesterase 4 (PDE4) inhibitors have been recently introduced as new modulators of intracellular signals and gene transcription for the treatment of IBD. Aim. To discuss and describe the state of the art of this new class of compounds in the IBD field, with particular attention to apremilast. Methods. Published articles selected from PubMed were comprehensively reviewed, with key words including apremilast, inflammatory disease, IBD, psoriasis, psoriatic arthritis, pathogenesis, therapies, and treatment. Results. PDE4 inhibitors generate elevated intracellular levels of cyclic Adenosine Monophosphate (cAMP), that consequently down-regulate the release of pro-inflammatory cytokines in the mucosa of IBD patients. The newly developed apremilast is one of these drugs and has already been approved for the treatment of dermatologic/rheumatologic inflammatory conditions; studies in psoriasis and psoriatic arthritis have in fact demonstrated its clinical activity. However, no clinical trials have yet been published on the use of apremilast in IBD. Conclusion. In light of the similarity of pro-inflammatory signaling pathways across the gut, the skin, and joints, apremilast is likely supposed to show its efficacy also in IBD.

Inhibition of phosphodiesterase‐4 attenuates murine ulcerative colitis through interference with mucosal immunity

“…Over the past decades, various PDE4 inhibitors, including rolipram, roflumilast, and tetomilast, have been introduced as new therapeutic attempts for the treatment of UC. Because of their severe side effects, including headache, vomiting, nausea, and other gastrointestinal problems, further clinical testing of rolipram and tetomilast was abandoned (Spadaccini et al, ). Roflumilast, approved for treating asthma and chronic obstructive pulmonary disease, is known to ameliorate the morphological and biochemical alterations in DSS‐induced colitis (El‐Ashmawy et al, ).…”

“…The phosphorylation of CREB and ATF-1 (lower part of e; lower part of f) and TNF-α (i) were measured. The summary data are shown as means ± SEM of three independent experiments problems, further clinical testing of rolipram and tetomilast was abandoned (Spadaccini et al, 2017). Roflumilast, approved for treating asthma and chronic obstructive pulmonary disease, is known to ameliorate the morphological and biochemical alterations in DSS-induced colitis (El-Ashmawy et al, 2018).…”

Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases

“…Tetomilast, another PDE4 specific inhibitor, was shown to inhibit the release of inflammatory mediators from activated human leukocytes and to alleviate the fundamentally observed symptoms, production of inflammatory cytokines, and colon histological scores in the IL-10-deficient colitis mice (Ichikawa et al, 2008 ). However, owing to the serious adverse effects, further investigations of the effect of PDE4 inhibitors in IBD have been slower than those for inflammatory airway and skin diseases (Bickston et al, 2012 ; Spadaccini et al, 2017 ).…”

Identification of a Selective PDE4B Inhibitor From Bryophyllum pinnatum by Target Fishing Study and In Vitro Evaluation of Quercetin 3-O-α-L-Arabinopyranosyl-(1→2)-O-α-L-Rhamnopyranoside

“…In contrast, the PDE4B inhibitors are widely known for their antiinflammatory action. This enzyme is the major cAMP-metabolizer found in cells of the inflammatory and immune system (Spadaccini et al, 2017) and it is differentiated from the other PDE4 isoforms by its high sensitivity towards the inhibitors (Azam and Tripuraneni, 2014). Among the four isoforms of phosphodiesterase 4 (A-D), PDE4B is believed to play a central role in inflammation, being characterized as the predominant subtype in monocytes and neutrophils (Azam and Tripuraneni, 2014;Yang et al, 2017).…”