Skin repair properties of d-Limonene and perillyl alcohol in murine models

• Published in: Anti-inflammatory & anti-allergy agents in medicinal chemistry Vol. 13; no. 1; p. 29
• Main Authors: d'Alessio, Patrizia A, Mirshahi, Massoud, Bisson, Jean-Francois, Bene, Marie C
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01.03.2014
• Subjects: Administration, Cutaneous; Angiogenesis Inhibitors - therapeutic use; Animals; Cells, Cultured; Citrus sinensis; Cyclohexenes - therapeutic use; Cytokines - blood; Dermatitis, Irritant - drug therapy; Disease Models, Animal; Endothelium - drug effects; Endothelium - pathology; Female; Fruit; Gene Expression Regulation - drug effects; Humans; Inflammation Mediators - blood; Mice; Mice, Hairless; Microtubules - drug effects; Monoterpenes - therapeutic use; P-Selectin - metabolism; Phorbol Esters - administration & dosage; Phytotherapy; Skin - drug effects; Skin - injuries; Skin - pathology; Terpenes - therapeutic use; Wound Healing - drug effects
• ISSN: 1875-614X

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.