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

Antiinflamm Antiallergy Agents Med Chem. 2014 Mar;13(1):29-35. doi: 10.2174/18715230113126660021.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Limonene
  • 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


  • Angiogenesis Inhibitors
  • Cyclohexenes
  • Cytokines
  • Inflammation Mediators
  • Monoterpenes
  • P-Selectin
  • Phorbol Esters
  • Terpenes
  • perillyl alcohol
  • Limonene