CNB-001, a synthetic pyrazole derivative of curcumin, suppresses lipopolysaccharide-induced nitric oxide production through the inhibition of NF-κB and p38 MAPK pathways in microglia

CNB-001, a pyrazole derivative of curcumin, has been found to exert neuroprotective and memory-enhancing effects that may be effective for the treatment of Alzheimer's disease. Since aberrant activation of microglia is involved in the pathogenesis of Alzheimer's disease, the present study was undertaken to investigate the effect of CNB-001 on microglia-mediated inflammatory responses. In primary cultured rat microglia, CNB-001 (1-10 mu M) suppressed the lipopolysaccharide (LPS)-induced nitric oxide (NO) production and expression of inducible NO synthase (iNOS), and the potency of CNB-001 was stronger than curcumin. CNB-001 also suppressed the LPSinduced nuclear translocation of nuclear factor kappa B (NF-kappa B), which is essential for the expression of iNOS. LPS treatment promoted phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK). CNB-001 significantly suppressed the LPS-induced phosphorylation of p38 MAPK, but not ERK and JNK. The suppressive effect of CNB-001 on NO production was mimicked by blockade of the p38 MAPK signaling pathway with SB203580. These results suggest that CNB-001 exerts anti-inflammatory effects through inhibition of NF-kappa B and p38 MAPK pathways in microglia.