We have previously reported that
NCX 2057, a new chemical entity bearing a
nitric oxide (NO)-releasing moiety linked to the natural
antioxidant ferulic acid, shows marked anti-inflammatory properties in a model of chronic
brain inflammation. We have now studied the effects of
NCX 2057 and its metabolic products,
ferulic acid and
NCX 2059, on
inducible nitric oxide synthase (iNOS) expression and function in
lipopolysaccharide/
interferon-gamma (LPS/IFNgamma)-stimulated RAW 264.7 macrophages.
NCX 2057 inhibited iNOS
mRNA and
protein expression (IC(50)=6.2+/-1.0 microM) without altering iNOS protein degradation rate.
NCX 2057 also decreased the levels of LPS/IFNgamma-induced
nitrite accumulation (IC(50)=4.3+/-0.7 microM) in RAW 264.7 cells. Conversely,
NCX 2059, which does not possess NO-donating properties, was only weakly effective (IC(50) >100 microM) and
ferulic acid was inactive. To understand further the mechanisms underlying anti-inflammatory properties we studied the effects of
NCX 2057 on selected
transcription factors. Unlike
ferulic acid,
NCX 2057 inhibited LPS-induced translocation/activation of the nuclear factor,
NF-kappaB, while other
transcription factors, such as, Sp1, NF-IL2A and STAT-1 were not affected. The present data support the concept that NO adds important anti-inflammatory properties to
ferulic acid. Thus,
NCX 2057 represents a new prototype
drug for the treatment of disorders associated with chronic
inflammation and oxidative stress.