Selective Cannabinoid Receptor-1 Agonists Regulate Mast Cell Activation in an Oxazolone-Induced Atopic Dermatitis Model

Abstract

BackgroundMany inflammatory mediators, including various cytokines (e.g. interleukins and tumor necrosis factor [TNF]), inflammatory proteases, and histamine are released following mast cell activation. However, the endogenous modulators for mast cell activation and the underlying mechanism have yet to be elucidated. Endogenous cannabinoids such as palmitoylethanolamide (PEA) and N-arachidonoylethanolamine (anandamide or AEA), were found in peripheral tissues and have been proposed to possess autacoid activity, implying that cannabinoids may downregulate mast cell activation and local inflammation.ObjectiveIn order to investigate the effect of cannabinoid receptor-1 (CB1R) agonists on mast cell activation, AEA-derived compounds were newly synthesized and evaluated for their effect on mast cell activation.MethodsThe effects of selected compounds on FcεRI-induced histamine and β-hexosaminidase release were evaluated in a rat basophilic leukemia cell line (RBL-2H3). To further investigate the inhibitory effects of CB1R agonist in vivo, an oxazolone-induced atopic dermatitis mouse model was exploited.ResultsWe found that CB1R inhibited the release of inflammatory mediators without causing cytotoxicity in RBL-2H3 cells and that CB1R agonists markedly and dose-dependently suppressed mast cell proliferation indicating that CB1R plays an important role in modulating antigen-dependent immunoglobulin E (IgE)-mediated mast cell activation. We also found that topical application of CB1R agonists suppressed the recruitment of mast cells into the skin and reduced the level of blood histamine.ConclusionOur results indicate that CB1R agonists down-regulate mast cell activation and may be used for relieving inflammatory symptoms mediated by mast cell activation, such as atopic dermatitis, psoriasis, and contact dermatitis.

A Guide to Targeting the Endocannabinoid System in Drug Design

“…Increased expression of CB1 was shown to promote oxidative stress and inflammation [201]. Contrarily, CB1 agonists decreased mast cell activation in vitro, exhibiting also anti-inflammatory activity in the rodent model, and are proposed as anti-inflammatory agents in psoriasis and dermatitis [202]. Moreover, as we showed above, CB1 agonists exhibit anti-neuroinflammatory properties.…”

Tetrahydrocannabinol Reduces Hapten-Driven Mast Cell Accumulation and Persistent Tactile Sensitivity in Mouse Model of Allergen-Provoked Localized Vulvodynia

“…Gaffal and colleagues have demonstrated the anti-inflammatory activity of THC, the main psychoactive phyto-cannabinoid of cannabis, in DNFB-driven dermatitis in mice [16]. Others have elucidated the effects of THC on mast cell function in oxazolone-driven dermatitis [17]. Here we tested the potential of THC, administered topically inside the vaginal canals of DNFB-challenged mice, to alleviate tactile sensitivity and reduce mast cell accumulation.…”

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

“…Two major CBRs are CB1 and CB2, and recently another G protein-coupled cannabinoid receptor, GPR55, has emerged as a type 3 CBR [58]. 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].…”