1. Academic Validation
  2. Anti-inflammatory effects of a novel phosphodiesterase-4 inhibitor, AA6216, in mouse dermatitis models

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

  • Eur J Pharmacol. 2021 Sep 5;906:174258. doi: 10.1016/j.ejphar.2021.174258.
Natsuki Kubota-Ishida 1 Takashi Matsuhira 2 Chizuko Kaji 2 Chika Kikuchi 2 Yuji Tabata 2
Affiliations

Affiliations

  • 1 Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama, 222-8567, Japan. Electronic address: natsuki.ishida@meiji.com.
  • 2 Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama, 222-8567, Japan.
Abstract

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.

Keywords

AA6216; Atopic dermatitis; Dermatitis; Phosphodiesterase 4 inhibitor.

Figures
Products