N-retinoyl-D-glucosamine, a new retinoic acid agonist, mediates topical retinoid efficacy with no irritation on photoaged skin.
BACKGROUND
Chronic ultraviolet (UV) radiation from sunlight induces wrinkle formation. Retinoic acid (RA) can markedly improve wrinkles, although RA does have some side-effects, such as skin irritation. As the efficacy and cytotoxicity of RA has been traced to its free carboxylic acid, we synthesized a new molecule, N-retinoyl-D-glucosamine (GRA), in which a glucosamine has been attached to the polar end group of all-trans retinoic acid.


OBJECTIVE
To analyse the effect of topical GRA in wrinkle repair and anti-irritation in photoaged mice compared with topical RA, as well as to determine retinoic acid receptor (RAR) and retinoid X receptor (RXR) transactivation activity in vitro.


METHODS
Hairless mice were irradiated with 60 mJ cm-2 of UVB for 10 weeks, and then topically treated with 0.05% GRA or 0.05% RA for 8 weeks. An in vitro transcriptional assay was performed and the activity of GRA in 293 cells transfected with RAR-alpha or RXR-alpha expression plasmid and luciferase reporter plasmid then determined.


RESULTS
Topical GRA and RA brought about almost complete disappearance of the wrinkles caused by UVB irradiation. The two ligands promoted both a wide repair zone histologically, and the expression of type 1 collagen in the skin. In contrast, topical GRA treatment did not produce irritation such as erythema or roughness, or alteration of transepidermal water loss values, compared with RA. In the in vitro luciferase assay, GRA resulted in significant dose-dependent RAR transactivation activity in a 100 times higher concentration range than RA. GRA did not mediate RXR transactivation activity at all.


CONCLUSIONS
Topical GRA appears to be able to repair photoaged skin damage without any of the irritation caused by topical RA, probably via RAR transactivation activity.
Kambayashi
H
H
Division of Dermatology, Department of Clinical Molecular Medicine, Translational Medicine, Faculty of Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. khiro@lion.co.jp
Odake
Y
Y
Takada
K
K
Funasaka
Y
Y
Ichihashi
M
M
Kato
S
S
D000287:Administration, Topical; D000818:Animals; D002460:Cell Line; D024042:Collagen Type I / Q000235:genetics; D017364:Collagenases / Q000235:genetics; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D012333:RNA, Messenger / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D012176:Retinoids / Q000819:agonists* / Q000737:chemistry / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000187:drug effects / Q000528:radiation effects; D015595:Skin Aging / Q000187:drug effects*; D014162:Transfection / Q000379:methods; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use
D024042:Collagen Type I; C508934:N-retinoylglucosamine; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D014212:Tretinoin; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D017364:Collagenases; D005944:Glucosamine