Topical application of a novel, hydrophilic γ-tocopherol derivative reduces photo-inflammation in mice skin

Abstract

We previously demonstrated that a novel hydrophilic γ-tocopherol (γ-Toc) derivative, γ-tocopherol-N,N-dimethylglycinate hydrochloride (γ-TDMG) converts to γ-Toc in the mouse skin and has a higher bioavailability than γ-Toc itself. In the present study, we determined whether γ-TDMG could reduce photo-inflammation in mouse skin, and compared its effectiveness to that of α-Toc acetate (α-TA). Topical pre- or post-application of 5% γ-TDMG significantly reduced the formation of edema and tempered the increase in cyclooxygenase-2 (COX-2)-catalyzed synthesis of prostaglandin E2 (PGE2) that were induced by a single dose of UV irradiation of 2 kJ/m2 (290-380 nm, maximum 312 nm). The pre-treatment of mouse skin with 10% α-TA had the same anti-inflammatory effect as did γ-TDMG. In spite of same having the ability to reduce PGE2 levels, the effect of γ-TDMG pre-treatment on the inhibition of COX-2 mRNA/protein expression was less than that seen with 10% α-TA. In contrast, the increase in COX-2 activity seen after UV exposure was reduced more by γ-TDMG than by α-TA, suggesting that the reduction in PGE2 levels might have been due to the direct inhibition of COX-2 activity by γ-TDMG-derived γ-Toc. Both Toc derivatives strongly suppressed inducible nitric oxide synthase (iNOS) mRNA expression and nitric oxide (NO) production, both of which play important roles in UV-induced inflammation. Both derivatives also significantly reduced lipid peroxidation in response to UV exposure, though γ-TDMG's ability in this regard was less than that seen with α-TA, which correlated with their abilities to suppress COX-2 expression. Thus, the γ-TDMG-derived γ-Toc acts as an antioxidant, suppresses iNOS expression and directly inhibits COX-2 activity, all of which likely play a role in mediating its suppressive effects on photo-inflammation. Our data further suggest that the topical application of γ-TDMG, a novel hydrophilic γ-Toc derivative, may be efficacious in preventing and reducing UV-induced inflammation in humans. © 2006 The Society for Investigative Dermatology.