Bicyclic monoterpene diols stimulate release of nitric oxide from skin cells, increase microcirculation, and elevate skin temperature

Bicyclic monoterpene diols (BMTd) stimulate nitric oxide synthesis in melanoma and neuronal cells, representing cell types arising from embryonic neural crest tissue. This study shows that an equimolar mixture of the BMTd's 2,3-cis/exo-pinanediol and 2,3-cis/exo-camphanediol stimulates nitric oxide synthesis in epithelial cells of the skin, specifically normal human epidermal keratinocytes (NHEK) and normal human microvascular endothelial cells (HMVEC). A 1 mM mixture increased nitric oxide 3-fold in HMVEC in the first 24 h after treatment, and a 2 mM mixture produced an equivalent increase in NHEK. We hypothesized that an increase in nitric oxide in skin would lead to an increase in microcirculation, thereby increasing skin temperature. We found that twice daily application of 1 mM BMTd lotion significantly increased arm skin temperature by 0.5 °C in 14 days compared to placebo, while a 2 mM mixture significantly increased skin temperature by 0.3 °C in 7 days (P ⩽ 0.05; ANOVA). A single application of a 2 mM BMTd mixture applied 30 min before a 30 min cold challenge (6 °C), maintained facial skin temperature 1.4 °C above untreated control sites (P ⩽ 0.05; ANOVA). We also tested whether BMTd treatment would benefit people with dark circles under their eyes. Twenty-six panelists with dark undereye circles completed 2-week, twice daily application of a lotion containing the 1 mM mixture to one eye while the other eye was untreated. Seven of 26 subjects showed a reduction of darkness of undereye circles (P ⩽ 0.05; paired t test). Application of 2 mM BMTd lotion to lips resulted in a significant increase in their redness, as measured by the erythema index (P ⩽ 0.05; ANOVA). These results show that a mixture of BMTd's increases nitric oxide, and application to skin increases microcirculation and skin temperature.