The Inhibitory Effect of S-777469, a Cannabinoid Type 2 Receptor Agonist, on Skin Inflammation in Mice

Abstract

We investigated the effects of S-777469 (1-[[6-Ethyl-1-[4-fluorobenzyl]-5-methyl-2-oxo-1, 2-dihydropyridine-3-carbonyl]amino]-cyclohexanecarboxylic acid), a novel cannabinoid type 2 receptor (CB2) agonist, on 1-fluoro-2,4-dinitrobenzene (DNFB)-induced ear inflammation and mite antigen-induced dermatitis in mice. The oral administration of S-777469 significantly suppressed DNFB-induced ear swelling in a dose-dependent manner. In addition, S-777469 significantly alleviated mite antigen-induced atopic dermatitis-like skin lesions in NC/Nga mice. A histological analysis revealed that S-777469 significantly reduced the epidermal thickness and the number of mast cells infiltrating skin lesions. We demonstrated that S-777469 inhibited mite antigen-induced eosinophil accumulation in skin lesions and an endogenous CB2 ligand, 2-arachidonoylglycerol (2-AG)-induced eosinophil migration in vitro. Moreover, we confirmed that 2-AG levels significantly increased in skin lesions of mite antigen-induced dermatitis model. Together, these results suggest that S-777469 inhibits skin inflammation in mice by blocking the activities of 2-AG.

The exogenous administration of CB2 specific agonist, GW405833, inhibits inflammation by reducing cytokine production and oxidative stress

“…As seen in macroscopic analysis, the effect of the COX inhibitor diclofenac was similar to anti-inflammatory effect of CB2 agonist. Haruna et al (34), have showed that the S-777469, (CB2) agonist, reduced the epidermal thickness and the number of mast cells infiltrating skin lesions of DNFB-induced ear swelling in mice. MAGL inhibition in diseased mice increased 2-arachidonoylglycerol levels, leading to a reduction of macroscopic and histological colon alterations in the trinitrobenzene sulfonic acid (TNBS)-induced colitis (31).…”

Cannabinoid receptor types 1 and 2 and peroxisome proliferator‐activated receptor‐α: distribution in the skin of clinically healthy cats and cats with hypersensitivity dermatitis

“…The endocannabinoid system is involved in attenuation of the skin allergic response: in mice with experimentally induced skin allergy, genetic ablation of CBR1 and CBR2 resulted in a more severe dermatitis and higher skin levels of PEA compared with wild‐type counterparts . Furthermore, CBR1 inhibited epidermal keratinocyte growth and different CBR2 agonists reduced skin inflammation in several experimental models of allergy . As such, the increased CBR1 and CBR2 expression in feline HD skin, as well as CBR2 immunoreactivity of dermal resident and infiltrating cells might be regarded as a skin response to inflammation, aimed at restoring homeostasis.…”

“…CBR1 and CBR2 also are overexpressed in the skin of dogs affected with atopic dermatitis . Implications for skin protective action of cannabinoid receptor agonists have been repeatedly suggested, and CB receptors are considered to play a crucial role in epidermal differentiation and recovery of the epidermal permeability barrier . Currently, evidence suggests that agonism at CB and CB‐related receptors may represent a novel treatment approach to common inflammatory/allergic skin diseases …”

Effect of Hataedock Treatment on Epidermal Structure Maintenance through Intervention in the Endocannabinoid System

“…Several studies have shown that CB1 agonists relieve inflammatory symptoms [59] by downregulating mast cell activation [60] and decreasing keratinocyte-derived proinflammatory mediators [61]. In addition, CB2 agonists suppress skin inflammation by inhibiting inflammatory cell migration [62], and GPR55, which is found in mast cells, has anti-inflammatory effects by inhibiting mast cell-mediated release of nerve growth factor and reducing angiogenesis [63]. In our study, the results indicate that HTD generates ECS components such as CB1, CB2, and GPR55.…”