Falcarindiol impairs the expression of inducible nitric oxide synthase by abrogating the activation of IKK and JAK in rat primary astrocytes

1 The effects of falcarindiol on the expression of inducible nitric oxide synthase (iNOS) induced by lipopolysaccharide/interferon-γ (LPS/IFN-γ) in rat primary astrocytes were investigated. The molecular mechanisms underlying falcarindiol that confers its effect on iNOS expression were also elucidated. 2 Falcarindiol abrogated the LPS/IFN-γ-mediated induction of iNOS by about 80%. Falcarindiol attenuated the induction of iNOS in a concentration-dependent manner. 3 The inhibitory effect of falcarindiol on iNOS induction was attributable to decrease in the protein content and the mRNA level of iNOS. 4 Treatment with 50 μM of falcarindiol for 30 min decreased LPS/IFN-γ-induced nuclear factor-κB (NF-κB) activation by 32%. 5 Treatment with 50 μM of falcarindiol for 60 min diminished the LPS/IFN-γ-mediated activation of IκB kinase-α (IKK-α) and IKK-β by 28.2 and 29.7%, respectively. 6 Falcarindiol modulated the nuclear translocation of signal transducer and activator of transcription 1 (Stat1) in a time-dependent manner. Falcarindiol (50 μM) decreased the tyrosine phosphorylation of janus kinase 1 (JAK1) by 84.8% at 5 min. Falcarindiol also abrogated the tyrosine phoshorylation of JAK2 by 82.3% at 10 min. 7 The present study demonstrates that falcarindiol attenuated the activation of IKK and JAK contributing to the blockade of activation of NF-κB and Stat1, thereby leading to the suppression of iNOS expression. British Journal of Pharmacology (2005) 144, 42–51. doi:10.1038/sj.bjp.0706022