Effects of resveratrol and its derivatives on lipopolysaccharide-induced microglial activation and their structure–activity relationships

Abstract

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 μM in sodium nitroprusside (SNP) solution. Moreover, compounds 2, 18, and 19 could also significantly inhibit the production of TNF-α by LPS-activated microglia. Further studies revealed that compounds 2, 18, and 19 inhibited LPS-induced NO and TNF-α production in microglia by blocking IκBα 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.