Abstract
Degradation of cyclic adenosine mono phosphate (cAMP) by phosphodiesterase-4B (PDE-4B) in the inflammatory cells leads to elevated expression of inflammatory cytokines in inflammatory cells. Suppression of cytokines has proved to be beneficial in the treatment of atopic dermatitis (AD). Henceforth, application of PDE4B specific inhibitor to minimize the degradation of cAMP can yield better results in the treatment of AD. PDE4B specific inhibitor with a limited side effect is highly warranted. Herein, we synthesized a novel PDE4 inhibitor, compound 2 comprising catecholopyrimidine core functionalized with trifluoromethyl (-CF3) group. PDE4B inhibitory potential and specificity of novel compounds were evaluated by PDE inhibitor assay. In vivo efficacy of the compounds was analyzed using DNCB-induced NC/Nga mice. IgE, CD4+ T-helper cell infiltration, and cytokine profiles were analyzed by ELISA and immunohistochemistry techniques. Toluidine blue staining was performed for mast cell count. PDE4 inhibitor assay confirmed that compound 2 specifically inhibits PDE4B. In vivo analysis with DNCB-induced NC/Nga mice confirmed that compound 2 suppressed the levels of pro-inflammatory cytokines such as TNF-α, IL-4, IL-5, and IL-17. Furthermore, compound 2 significantly reduced the infiltrative CD4+ T-helper cells, mast cells and IgE levels in atopic tissue. The in vitro and in vivo data suggested that compound 2 specifically inhibit the PDE4B and the symptoms of the AD in atopic mice. Compound 2 might constitute a good candidate molecule for the treatment of AD.
Highlights
Atopic dermatitis (AD) is an inflammatory skin disease that affects young children (Beasley, 1998; Odhiambo et al, 2009)
Observed results show that compound 2 exhibited high specificity against PDE4B compared to other PDE enzymes utilized in the study
The observed results of the present study indicate that compound 1 and 2 significantly suppressed the expression of DNCB-induced IL-17, which shows the possible involvement of cyclic adenosine mono phosphate (cAMP)-mediated signaling in the regulation of Th17 cells
Summary
Atopic dermatitis (AD) is an inflammatory skin disease that affects young children (Beasley, 1998; Odhiambo et al, 2009). Unbearable itching is the major symptom of the AD. It leads to the psychological difficulties such as anxiety, anger, and depression (Simpson et al, 2016). Disruption of epidermal structure and infiltration of abnormal levels of T-helper cells, neutrophils, and mast cells into the dermis are the major pathophysiology of the AD (Wu et al, 2015). Activated lymphocytes at the dermis region constitutively secrete abnormal levels of inflammatory cytokines and contribute to the inflammation of the skin (Boguniewicz and Leung, 2011). Long-term administration of PDE4B Selective Inhibitor for Dermatitis corticosteroids is required to treat AD, it eventually leads to the systemic side effects and cutaneous atrophy. Alternative therapy is required to minimize the treatment duration and side effects
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