Skin Repair Properties of d-Limonene and Perillyl Alcohol in Murine Models
Patrizia A. d'Alessio, Massoud Mirshahi, Jean-Francois Bisson and Marie C. Bene
Affiliation: Biopark Campus Cancer, 1, mail Pr Georges Mathe, 94807 Villejuif – France.
Keywords: Angiogenesis inhibition, d-Limonene, inflammation inhibition, P-selectin, wound healing.
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.
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