Article ID Journal Published Year Pages File Type
2200240 Neurochemistry International 2016 9 Pages PDF
Abstract

•CRPE55IB inhibits LPS induced neuroinflammatory response in microglia.•CRPE55IB inhibits LPS-induced NF-κB activation in microglia.•Nrf2 mediates the anti-neuroinflammation of CRPE55IB in microglia.•AMPK mediates the anti-neuroinflammatory effects of CRPE55IB in microglia.

Polygonum multiflorum extracts are known to improve memory and learning ability, and have neuroprotective and anti-aging activity. However, its function and the underlying mechanisms in neuroinflammation-mediated neurodegenerative disease remain poorly understood. In the present study, we investigated the anti-neuroinflammatory effects of several compounds from P. multiflorum, and found a novel compound, CRPE55IB. The CRPE55IB-induced suppression of NO and PGE2 production correlated with inhibition of iNOS and COX-2 protein expression and promoter activity in lipopolysaccharide (LPS)-stimulated microglia. CRPE55IB also reduced the production of pro-inflammatory cytokines (TNF-α and IL-6) induced by LPS. Furthermore, investigation of the molecular mechanism indicated that CRPE55IB inhibited LPS-induced NF-κB activation by inactivating phosphorylation of IKKα/β, and phosphorylation and degradation of IκBα. We further found that CRPE55IB inhibited the phosphorylation of ERK and JNK at a lower concentration than that for p38 MAPK. Further experiments revealed that CRPE55IB treatment considerably increased the activation of Nrf2/ARE, and the expression of its target genes, including HO-1 and NQO1. Moreover, the Knockdown of Nrf2, HO-1, and NQO1 by siRNA abrogated the inhibitory effect of CRPE55IB on iNOS and COX-2 promoter activity. CRPE55IB also induced phosphorylation of AMPK/LKB/CaMKII in microglia. Analysis using a specific inhibitor of AMPK demonstrated that AMPK activation was involved in CRPE55IB-induced HO-1 and NQO1 expression. In addition, the CRPE55IB-induced anti-neuroinflammatory effect was abrogated by a specific inhibitor of AMPK, indicating the important role of AMPK in CRPE55IB-induced anti-neuroinflammation. Collectively, these results demonstrate that CRPE55IB exerts anti-neuroinflammatory effects against LPS via the Nrf2/AMPK signaling pathways.

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