Abstract
It 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 laboratory of Prof. Mechoulam has recently synthesized a series of fluorinated derivatives of cannabidiol (CBD), the major non-psychoactive component of the plant Cannabis sativa. The goal of the current study was to assess the potential cutaneous anti-inflammatory actions of these compounds (F-CBDs). Effects of CBD and F-CBDs (HUF-101, HUF-103 and HU-559a) were investigated in seven, previously established in vitro human epidermal keratinocyte models (employing the immortalized HaCaT and HPV-KER keratinocyte cell lines) which mimic, as closely as possible, various human inflammatory skin conditions and diseases (e.g. microbial, UVB-induced, allergic, contact, and atopic dermatitis). Gene expression and protein release were assessed by RT-qPCR and ELISA, respectively. As expected, 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 F-CBDs in most models. Of great importance, however, all F-CBDs exhibited significantly higher efficacies in comparison to the non-fluorinated counterpart CBD, with the rank order of efficacy in the in vitro human epidermal keratinocyte models being HUF103 > HU559a > HU101. Our study provides the first evidence that F-CBDs exert remarkable anti-inflammatory actions on human epidermal keratinocytes. These intriguing data invite further pre-clinical and clinical studies to exploit the therapeutic potential of certain F-CBDs in a various cutaneous inflammatory conditions.
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