Prevention of ocular inflammation in endotoxin-induced uveitis with resveratrol by inhibiting oxidative damage and nuclear factor-kappaB activation.
OBJECTIVE
Resveratrol is known as one of the antioxidant polyphenols contained in red wine and grape skin. The purpose of the present study was to investigate the role of resveratrol in ocular inflammation in endotoxin-induced uveitis (EIU).


METHODS
EIU was induced in male C57/B6 mice at the age of 6 weeks by a single intraperitoneal injection of lipopolysaccharide (LPS). Animals had received oral supplementation of resveratrol at the doses of 5, 50, 100, or 200 mg/kg for 5 days until LPS injection. Twenty-four hours after LPS administration, leukocyte adhesion to the retinal vasculature was examined with a concanavalin A lectin perfusion-labeling technique. Retinal and retinal pigment epithelium (RPE)-choroidal levels of intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nuclear translocation of nuclear factor (NF)-kappaB p65 were evaluated by enzyme-linked immunosorbent assay. Retinal and RPE-choroidal activities of silent information regulator two ortholog (SIRT) 1 were measured by deacetylase fluorometric assay.


RESULTS
Resveratrol pretreatment led to significant and dose-dependent suppression of leukocyte adhesion to retinal vessels of EIU mice compared with vehicle application. Protein levels of MCP-1 and ICAM-1 in the retina and the RPE-choroid of EIU animals were significantly reduced by resveratrol administration. Importantly, resveratrol-treated animals showed significant decline of retinal 8-OHdG generation and nuclear NF-kappaB P65 translocation, both of which were upregulated after EIU induction. RPE-choroidal SIRT1 activity, reduced in EIU animals, was significantly augmented by treatment with resveratrol.


CONCLUSIONS
Resveratrol prevented EIU-associated cellular and molecular inflammatory responses by inhibiting oxidative damage and redox-sensitive NF-kappaB activation.
Kubota
Shunsuke
S
Department ofOphthalmology, Laboratory of Retinal Cell Biology, Keio University School of Medicine, Tokyo, Japan.
Kurihara
Toshihide
T
Mochimaru
Hiroshi
H
Satofuka
Shingo
S
Noda
Kousuke
K
Ozawa
Yoko
Y
Oike
Yuichi
Y
Ishida
Susumu
S
Tsubota
Kazuo
K
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli; D019084:Fluorescent Antibody Technique, Indirect; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress / Q000187:drug effects*; D000077185:Resveratrol; D012160:Retina / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D012171:Retinal Vessels / Q000378:metabolism; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism; D013267:Stilbenes / Q000008:administration & dosage*; D051996:Transcription Factor RelA / Q000378:metabolism; D014605:Uveitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
D000975:Antioxidants; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D008070:Lipopolysaccharides; D016328:NF-kappa B; D013267:Stilbenes; D051996:Transcription Factor RelA; D018799:Intercellular Adhesion Molecule-1; D000080242:8-Hydroxy-2'-Deoxyguanosine; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins; D003849:Deoxyguanosine; D000077185:Resveratrol