Beta-caryophyllene enhances wound healing through multiple routes

Abstract

Beta-caryophyllene is an odoriferous bicyclic sesquiterpene found in various herbs and spices. Recently, it was found that beta-caryophyllene is a ligand of the cannabinoid receptor 2 (CB2). Activation of CB2 will decrease pain, a major signal for inflammatory responses. We hypothesized that beta-caryophyllene can affect wound healing by decreasing inflammation. Here we show that cutaneous wounds of mice treated with beta-caryophyllene had enhanced re-epithelialization. The treated tissue showed increased cell proliferation and cells treated with beta-caryophyllene showed enhanced cell migration, suggesting that the higher re-epithelialization is due to enhanced cell proliferation and cell migration. The treated tissues also had up-regulated gene expression for hair follicle bulge stem cells. Olfactory receptors were not involved in the enhanced wound healing. Transient Receptor Potential channel genes were up-regulated in the injured skin exposed to beta-caryophyllene. Interestingly, there were sex differences in the impact of beta- caryophyllene as only the injured skin of female mice had enhanced re-epithelialization after exposure to beta-caryophyllene. Our study suggests that chemical compounds included in essential oils have the capability to improve wound healing, an effect generated by synergetic impacts of multiple pathways.

The Effects of Essential Oils and Terpenes in Relation to Their Routes of Intake and Application

“…As β-caryophyllene activates several different types of receptors other than olfactory receptors, the impact on improving re-epithelialization can be mediated by activating other routes. In these studies [2], although β-caryophyllene is known as a cannabinoid receptor 2 (CB2) ligand [5], the CB2 gene was down-regulated in skin 17 h post-injury+β-caryophyllene-application, whereas transient receptor potential cation channel subfamily melastatin (TRPM1, TRPM6), and transient receptor potential cation channel subfamily vanilloid (TRPV4, TRPV6) were significantly up-regulated [2]. This suggests the possibility of the involvement of these channels in improving wound healing.…”

“…Studies using mice have found that the essential oil of oleoresin, Copaifera paupera, which contains β-caryophyllene, improves wound healing [68], although it was not clear in that study whether β-caryophyllene produced the impact nor whether an olfactory receptor was involved. Studies using β-caryophyllene (and not essential oils that contain β-caryophyllene) have shown that, topical application of β-caryophyllene on cutaneous wounds can improve re-epithelialization, but the olfactory system was not involved in the impact [2]. As β-caryophyllene activates several different types of receptors other than olfactory receptors, the impact on improving re-epithelialization can be mediated by activating other routes.…”

“…This suggests the possibility of the involvement of these channels in improving wound healing. RNA sequencing and pathway analyses of skin exposed to β-caryophyllene showed that the pathways related to cell proliferation and cell migration were significantly activated (the sonic hedgehog pathway, the planar cell polarity signaling pathway, the fibroblast growth factor signaling pathway, and the Wnt β-catenin signaling pathway) [2]. Studies have found that hedgehog signaling is involved in epidermal homeostasis [69] and that sonic hedgehog secreted from sensory neurons surrounding the hair follicle bulge stimulates Gli1+ (a hair follicle bulge marker) cells in the upper hair follicle bulge to convert to multipotent stem cells, which will migrate to the epidermis and contribute to re-epithelialization [70].…”

“…In the incident that inspired René-Maurice Gattefossé [1] to study the functions of essential oils and the chemical constituents that are involved, the anecdotal story goes that he noticed less scar formation on his burnt hand. In the studies in which β-caryophyllene was topically applied to a cutaneous wound, many genes related to embryonic growth were found up-regulated (cell migration (e.g., Adamts), cell fate determination, and hair follicle formation (Bambi, Msx2, Dlx3, Padi1, Hoxc13, S100a)) [2], suggesting the possibility of more complete skin regeneration. In the field of scar formation and regeneration, embryonic growth is a topic of strong interest because of the more complete regeneration (lack of scars) in injured embryos (personal communication with Dr. Anthony Mescher of Indiana University, School of Medicine who studies regeneration).…”

“…OW 400-800: out of wound bed, 400 to 800 um. (C) LGR5 (red) expression was stronger in the skin post-wound day 4 exposed to β-caryophyllene, compared to oil group control (from [2]). The dotted line indicates the wound edge.…”