Topical application of a novel, hydrophilic gamma-tocopherol derivative reduces photo-inflammation in mice skin.
We previously demonstrated that a novel hydrophilic gamma-tocopherol (gamma-Toc) derivative, gamma-tocopherol-N,N-dimethylglycinate hydrochloride (gamma-TDMG) converts to gamma-Toc in the mouse skin and has a higher bioavailability than gamma-Toc itself. In the present study, we determined whether gamma-TDMG could reduce photo-inflammation in mouse skin, and compared its effectiveness to that of alpha-Toc acetate (alpha-TA). Topical pre- or post-application of 5% gamma-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% alpha-TA had the same anti-inflammatory effect as did gamma-TDMG. In spite of same having the ability to reduce PGE2 levels, the effect of gamma-TDMG pre-treatment on the inhibition of COX-2 mRNA/protein expression was less than that seen with 10% alpha-TA. In contrast, the increase in COX-2 activity seen after UV exposure was reduced more by gamma-TDMG than by alpha-TA, suggesting that the reduction in PGE2 levels might have been due to the direct inhibition of COX-2 activity by gamma-TDMG-derived gamma-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 gamma-TDMG's ability in this regard was less than that seen with alpha-TA, which correlated with their abilities to suppress COX-2 expression. Thus, the gamma-TDMG-derived gamma-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 gamma-TDMG, a novel hydrophilic gamma-Toc derivative, may be efficacious in preventing and reducing UV-induced inflammation in humans.
Department of Molecular Physiology, Kyoritsu University of Pharmacy, Tokyo, Japan.
Emiko
E
Yoshida
Tatsuya
T
Watanabe
Jiro
J
Takata
Akihiko
A
Yamazaki
Yoshiharu
Y
Karube
Shizuko
S
Kobayashi
D000287:Administration, Topical; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004817:Epidermis / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008812:Mice, Hairless; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D024505:Tocopherols; D014466:Ultraviolet Rays / Q000009:adverse effects; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000032:analysis / Q000494:pharmacology; D024504:gamma-Tocopherol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000975:Antioxidants; D016861:Cyclooxygenase Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C512054:gamma-tocopherol-N,N-dimethylglycinate hydrochloride; D009569:Nitric Oxide; D024504:gamma-Tocopherol; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2; D024502:alpha-Tocopherol; D015232:Dinoprostone; D024505:Tocopherols; D005998:Glycine; D007213:Indomethacin