Quercetin inhibits lipopolysaccharide-induced nitric oxide production in BV2 microglial cells by suppressing the NF-κB pathway and activating the Nrf2-dependent HO-1 pathway.

Abnormal nitrosative stress-induced neuroinflammation is implicated in the pathogenesis of neurodegenerative diseases. Therefore, it has been thought that nitric oxide (NO) production is a good therapeutic target. In this sense, quercetin is a good chemopreventive component, because it has free radical-scavenging and anti-inflammatory activities. However, explicit mechanisms are not clear in the lipopolysaccharide (LPS)-stimulated BV2 microglial cell line. Here, we found that quercetin significantly suppressed LPS-induced NO production and inducible NO synthase (iNOS) expression. Notably, quercetin inhibited nuclear factor-κB (NF-κB) activation by inhibiting degradation of the inhibitor of kappa Bα (IκBα) in LPS-stimulated BV2 microglial cells corresponding to the inhibitory effect of specific NF-κB inhibitors, namely proteasome inhibitor I (PSI) and MG132. Quercetin caused significant increases in the levels of heme oxgenase-1 (HO-1) mRNA and protein. Notably, treatment with an HO-1 inducer, cobalt protoporphyrin (CoPP), significantly diminished LPS-stimulated NO production. Additionally, quercetin induced the specific DNA-binding activity of nuclear factor-2-erythroid 2-related factor 2 (Nrf2), and siRNA-mediated knockdown of Nrf2 expression reduced the inhibitory effect of quercetin on LPS-stimulated NO production by inhibiting HO-1 expression, indicating that quercetin regulated NO production by inducing Nrf2-mediated HO-1 expression. Therefore, quercetin has the potential to decrease nitrosative stress by suppressing NF-κB activation and inducing Nrf2-mediated HO-1 expression.