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.