Anti-inflammatory effects of a novel phosphodiesterase-4 inhibitor, AA6216, in mouse dermatitis models

• Published in: European journal of pharmacology Vol. 906; p. 174258
• Main Authors: Kubota-Ishida, Natsuki, Matsuhira, Takashi, Kaji, Chizuko, Kikuchi, Chika, Tabata, Yuji
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.09.2021
• Subjects: AA6216; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Atopic dermatitis; Boron Compounds - pharmacology; Boron Compounds - therapeutic use; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Dermatitis; Dermatitis, Atopic - chemically induced; Dermatitis, Atopic - diagnosis; Dermatitis, Atopic - drug therapy; Dermatitis, Atopic - immunology; Dermatophagoides farinae - immunology; Disease Models, Animal; Female; Humans; Leukocytes, Mononuclear; Mice; Oxazoles - pharmacology; Oxazoles - therapeutic use; Oxazolone - administration & dosage; Oxazolone - toxicity; Phosphodiesterase 4 inhibitor; Phosphodiesterase 4 Inhibitors - pharmacology; Phosphodiesterase 4 Inhibitors - therapeutic use; Piperazines - pharmacology; Piperazines - therapeutic use; Severity of Illness Index; Skin - drug effects; Skin - immunology; Skin - pathology; Thiazoles - pharmacology; Thiazoles - therapeutic use; AA6216; Phosphodiesterase 4 inhibitor; Atopic dermatitis; Dermatitis
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2021.174258

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is commonly treated with corticosteroids. However, these drugs have long-term adverse effects, representing an unmet need for new treatments. AD is associated with dysregulation of phosphodiesterase 4 (PDE4) activity in inflammatory cells and the topical PDE4 inhibitor, crisaborole, is approved by the US FDA for mild-to-moderate AD. In this study, we compared the effects of a novel PDE4 inhibitor, AA6216, with those of crisaborole on skin inflammation. We found that AA6216 is a more potent inhibitor of PDE4 and of cytokine production (TNF-α, IL-12/23p40, IL-4, IL-13, and IFN-γ) by human peripheral blood mononuclear cells (PBMCs) stimulated by phytohemagglutinin (PHA) or anti-CD3 antibodies, with IC50 values ranging from 5.9 to 47 nM. AA6216 also significantly suppressed skin inflammation in three mouse models of dermatitis. In acute and chronic oxazolone-induced dermatitis models, topical AA6216 exhibited stronger inhibitory effects on ear inflammation and cytokine production (TNFα, IL-1β, and IL-4) in skin lesions compared with crisaborole. In a Dermatophagoides farinae-induced dermatitis model, AA6216 significantly reduced the dermatitis score, based on the development of erythema/hemorrhage, scarring/dryness, edema, and excoriation/erosion, compared with a clinically used topical AD drug, tacrolimus. These results suggest the possibility that AA6216 is a novel and effective topical therapeutic agent for the treatment of dermatitis including AD.