We previously demonstrated that a novel hydrophilic g-tocopherol (g-Toc) derivative, g-tocopherol-N, N-dimethylglycinate hydrochloride (g-TDMG) converts to g-Toc in the mouse skin and has a higher bioavailability than g-Toc itself. In the present study, we determined whether g-TDMG could reduce photoinflammation in mouse skin, and compared its effectiveness to that of a-Toc acetate (a-TA). Topical pre-or postapplication of 5% g-TDMG significantly reduced the formation of edema and tempered the

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... ncrease in cyclooxygenase-2 (COX-2)-catalyzed synthesis of prostaglandin E 2 (PGE 2 ) that were induced by a single dose of UV irradiation of 2 kJ/m 2 (290-380 nm, maximum 312 nm). The pre-treatment of mouse skin with 10% a-TA had the same anti-inflammatory effect as did g-TDMG. In spite of same having the ability to reduce PGE 2 levels, the effect of g-TDMG pre-treatment on the inhibition of COX-2 mRNA/protein expression was less than that seen with 10% a-TA. In contrast, the increase in COX-2 activity seen after UV exposure was reduced more by g-TDMG than by a-TA, suggesting that the reduction in PGE 2 levels might have been due to the direct inhibition of COX-2 activity by g-TDMG-derived g-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 g-TDMG's ability in this regard was less than that seen with a-TA, which correlated with their abilities to suppress COX-2 expression. Thus, the g-TDMG-derived g-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 photoinflammation. Our data further suggest that the topical application of g-TDMG, a novel hydrophilic g-Toc derivative, may be efficacious in preventing and reducing UV-induced inflammation in humans.