Effects of resveratrol and its derivatives on lipopolysaccharide-induced microglial activation and their structure-activity relationships.
The inhibitory effects of 21 resveratrol derivatives on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in microglia and their structure-activity relationships were studied. It was found, for the first time, that certain resveratrol derivatives that have 3,5-dimethoxyl groups in the A-ring, such as (E)-4-(3,5-dimethoxystyryl)phenol (pterostilbene, compound 2), or have substituted the B-ring of resveratrol with quinolyl, such as (E)-5-[2-(quinolin-4-yl)vinyl]benzene-1,3-diol (compound 18) and (E)-4-(3,5-dimethoxystyryl)quinoline (compound 19), strongly inhibited NO production. Compounds 2, 18, and 19 reduced LPS-induced protein and mRNA expression of inducible NO synthase (iNOS), but did not display direct NO-scavenging activity up to 30 microM in sodium nitroprusside (SNP) solution. Moreover, compounds 2, 18, and 19 could also significantly inhibit the production of TNF-alpha by LPS-activated microglia. Further studies revealed that compounds 2, 18, and 19 inhibited LPS-induced NO and TNF-alpha production in microglia by blocking IkappaBalpha phosphorylation and degradation. The potent inhibitory effects of compounds 2, 18, and 19 on microglial activation suggest their potential for treatment of neurodegenerative diseases accompanied by microglial activation.
Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
Xue-Lian
XL
Meng
Jing-Yu
JY
Yang
Guo-Liang
GL
Chen
Li-Hui
LH
Wang
Li-Jia
LJ
Zhang
Shu
S
Wang
Jie
J
Li
Chun-Fu
CF
Wu
D000818:Animals; D016166:Free Radical Scavengers / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020672:I-kappa B Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009599:Nitroprusside / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D012996:Solutions; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016166:Free Radical Scavengers; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; C000606206:Nfkbia protein, rat; D012333:RNA, Messenger; D012996:Solutions; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D009599:Nitroprusside; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D000077185:Resveratrol