Assessment of the anti-inflammatory effects of cannabidiol and its fluorinated derivative in in vitro and in vivo models of atopic dermatitis

Noémi Miltner1, Gabriella Béke1, Ágnes Angyal1, Ágnes Kemény2, Erika Pintér2, Zsuzsanna Helyes2, Tamás Bíró1,3, Johanna Mihály1Assessment of the anti-inflammatory effects of cannabidiol and its fluorinated derivative in in vitro and in vivo models of atopic dermatitis1Department of Immunology, Faculty of Medicine, University of Debrecen, Hungary2Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Hungary3Phytecs Inc., Los Angeles, CA, USAIt is common wisdom in pharmacology that fluorination can significantly increase the efficacy of the active components in pharmaceuticals – actually, ca. 30% of the best-selling drugs worldwide contain fluorinated compounds. The aim of the current study was to assess the potential anti-inflammatory effects of cannabidiol (CBD), the major non-psychoactive component of the pant Cannabis sativa, and its fluorinated derivative (HUF-101) in various experimental systems modeling atopic dermatitis (AD). For the in vitro AD model, human epidermal keratinocytes were challenged with the combination of Staphylococcus aureus enterotoxin B (SEB) and thymic stromal lymphopoietin (TSLP), and expressions of certain marker molecules were assessed by RT-qPCR and ELISA. For the in vivo model, mice were sensitized with 2% oxazolone (OXA) before elicitation. Test compounds were applied topically (1 and 10 μM) after inducing skin inflammation and edema formation (in the ears) was measured with an engineer’s micrometer.In the in vitro model, expressions of certain pro-inflammatory cytokines (e.g. interleukin [IL]-1α, IL-1β, IL-6 and IL-8) were significantly down-regulated upon the administration of CBD and HUF-101. Of great importance, however, HUF-101 exhibited significantly higher potency in comparison to CBD. In the in vivo model, topical application of 1 μM CBD significantly reduced the OXA-induced ear edema; however, 10 μM CBD exerted insignificant effect. In contrast, HUF-101 attenuated OXA-induced edema formation at both concentrations. Intriguingly, similar to the in vitro conditions, the anti-inflammatory potency of HUF-101 was significantly greater than that of CBD. Our study provides the first evidence that CBD and its fluorinated derivative exert significant anti-inflammatory actions in models of AD. These intriguing data invite further pre-clinical and clinical studies to exploit the therapeutic potential of certain CBD derivatives in cutaneous inflammatory conditions

Activation of Transient Receptor Potential Vanilloid 3 Regulates Inflammatory Actions of Human Epidermal Keratinocytes

Transient receptor potential (TRP) ion channels were first characterized on neurons, wherethey are classically implicated in sensory functions; however, research in recent decades hasshown that many of these channels are also expressed on non-neuronal cell types. Emergingfindings have highlighted the role of TRP channels in the skin, where they have been shownto be important in numerous cutaneous functions. Of particular interest is TRPV3, which wasfirst described on keratinocytes. Its functional importance was supported when its gain-offunctionmutation was linked to Olmsted syndrome, which is characterized by palmoplantarkeratoderma, periorifacial hyperkeratosis, diffuse hypotrichosis and alopecia, as well as itch.In spite of these exciting results, we have no information about the role and functionality ofTRPV3 on keratinocytes at the cellular level. In our current study, we have identified TRPV3expression both on human skin and cultured epidermal keratinocytes. TRPV3 stimulation wasfound to function as a Ca2+-permeable ion channel which suppresses proliferation ofepidermal keratinocytes and induces cell death. Stimulation of the channel also triggers astrong proinflammatory response via the NF-κB pathway. Collectively our data shows thatTRPV3 is functionally expressed on human epidermal keratinocytes and that it plays a role incutaneous inflammatory processes