Marked improvement induced in photoaged skin of hairless mouse by ER36009, a novel RARgamma-specific retinoid, but not by ER35794, an RXR-selective agonist.
BACKGROUND
Photoaging (premature skin aging) results largely from repeated exposure of the skin to ultraviolet (UV) radiation from the sun. Topical all-trans retinoic acid (RA), the only agent that has been approved for the treatment of photoaging, has been shown to reverse this process. In this study, we evaluated the pharmacologic effects of novel synthetic retinoids, ER36009 and ER35794, on murine wrinkles induced by UVB. ER36009 is a specific agonist of retinoic acid receptor (RAR)gamma, the most abundant RAR subtype in the skin, while ER35794 is a potent retinoid X receptor (RXR)-selective agonist.


METHODS
After a 10-week exposure to escalating doses of UVB irradiation, the animals were treated three times per week with ER36009 (0.0001%, 0.00025%, 0.0005%), ER35794 (0.025%, 0.05%, 0.1%), RA (0.05%) or acetone (control) for 3 weeks.


RESULTS
ER36009 exerted a dose-dependent wrinkle-effacing effect, and 0.0005% ER36009-treated skin was significantly different from the control. ER36009 also significantly and dose-dependently increased both epidermal thickness and the area of the dermal repair zone defined by newly synthesized collagen. The effect of 0.0005% ER36009 on photodamaged skin was superior to that of 0.05% RA. In contrast, ER35794 was inactive in this model, though this compound exhibited lower local toxicity than other retinoids.


CONCLUSIONS
These data indicate that RARgamma, but not RXR, plays an important role in the improvement of the signs of photoaging, and so a specific RARgamma agonist might be superior to an RAR pan-agonist for clinical treatment. We conclude that ER36009 is a candidate for a potent anti-skin-aging agent.
Sakuta
Tomohiro
T
SHISEIDO Pharmaceutical Research Center, Yokohama, Japan. tomohiro.sakuta@to.shiseido.co.jp
Kanayama
Toshiji
T
D000818:Animals; D020405:Dermis / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008812:Mice, Hairless; D015394:Molecular Structure; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology*; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D047488:Retinoid X Receptors / Q000819:agonists*; D012176:Retinoids / Q000737:chemistry / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D015595:Skin Aging / Q000187:drug effects* / Q000528:radiation effects; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D014466:Ultraviolet Rays / Q000009:adverse effects; D000097768:Retinoic Acid Receptor gamma
D005231:Fatty Acids, Unsaturated; D011804:Quinolines; D011810:Quinoxalines; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D013844:Thiazoles; D000097768:Retinoic Acid Receptor gamma; C516309:4-(4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-quinoxalinyl)-1,3-thiazol-2-yl)benzoic acid; C516310:7-(1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl)-6-fluoro-3-methylnona-2,4,6-trienoic acid