title: Skin repair properties of d-Limonene and perillyl alcohol in murine models.
abstract: The orange-peel derived terpene d-Limonene, probably through its metabolite, perillyl alcohol (POH), has been reported to have tissue-repair properties. Two murine models of respectively 12-O-Tetradecanoylphorbol-13-Acetate (TPA)-induced dermatitis and mechanical skin lesion were used here to assess the efficacy of d-Limonene or POH applied topically. Macroscopic and microscopic evaluation of skin lesions was performed as well as that of P-selectin expression, together with measurements of serum concentrations of IL-1β, IL-6 and TNF-α in the first model. Healing and angiogenesis around the scar were examined in the second model. Because differences in angiogenesis were noted, the effect of both d-Limonene and POH was further tested on an in vitro model of endothelial microtubules formation. Both d-Limonene and POH reduced the severity and extension of TPA-induced skin lesions with significantly lowered macroscopic and microscopic scores (p<0.04 in both cases). Moreover, the expression of P-selectin induced by TPA was abrogated by POH and significantly lower serum concentrations of IL-6 and TNF-α were observed in d-Limonene- and POH-treated mice (p<0.04 and 0.03). In the second model, tissue regeneration was improved, especially by POH, and was clearly associated with reduced neovascularization. This surprising anti-angiogenic effect was confirmed in the matrigel model of endothelial microtubules formation. These studies show that d-Limonene and POH demonstrate significant anti-inflammatory effects in murine dermal inflammation and wound-healing. The decreased systemic cytokine production as well as a consistent inhibition of endothelial P-selectin expression and neo-vascularization induced by these terpenic compounds contribute to their healing effects on the epidermal barrier.
authors.forename: Patrizia A
authors.initials: PA
authors.lastname: d'Alessio
authors.forename: Massoud
authors.initials: M
authors.lastname: Mirshahi
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Bisson
authors.affiliation: Biopark Campus Cancer, 1, mail Pr Georges Mathe, 94807 Villejuif - France. endocell@wanadoo.fr.
authors.forename: Marie C
authors.initials: MC
authors.lastname: Bene
mesh_terms: D000279:Administration, Cutaneous; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002478:Cells, Cultured; D032084:Citrus sinensis; D053138:Cyclohexenes / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood; D017453:Dermatitis, Irritant / Q000188:drug therapy*; D004195:Disease Models, Animal; D004727:Endothelium / Q000187:drug effects / Q000473:pathology; D005260:Female; D005638:Fruit; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D000077222:Limonene; D051379:Mice; D008812:Mice, Hairless; D008870:Microtubules / Q000187:drug effects; D039821:Monoterpenes / Q000627:therapeutic use*; D019007:P-Selectin / Q000378:metabolism; D010703:Phorbol Esters / Q000008:administration & dosage; D008517:Phytotherapy; D012867:Skin / Q000187:drug effects* / Q000293:injuries / Q000473:pathology; D013729:Terpenes / Q000627:therapeutic use*; D014945:Wound Healing / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D053138:Cyclohexenes; D016207:Cytokines; D018836:Inflammation Mediators; D039821:Monoterpenes; D019007:P-Selectin; D010703:Phorbol Esters; D013729:Terpenes; C032208:perillyl alcohol; D000077222:Limonene