Gingerol metabolite and a synthetic analogue Capsarol inhibit macrophage NF-kappaB-mediated iNOS gene expression and enzyme activity

Planta Med. 2006 Jun;72(8):727-34. doi: 10.1055/s-2006-931588. Epub 2006 May 29.


Ginger (Zingiber officinale) is widely used in traditional Chinese medicine, with beneficial effects reported in numerous diseases, including inflammation. Inducible nitric oxide synthase (iNOS), a proinflammatory enzyme responsible for the generation of nitric oxide (NO), has been implicated in the pathogenesis of inflammatory diseases. Gingerols, the main pungent principles of ginger, have anti-inflammatory properties in vitro. In this study we examine the inhibitory effect of a stable [6]-gingerol metabolite, RAC-[6]-dihydroparadol ([6]-DHP) and a closely related gingerol analogue, RAC-2-hydroxy-1-(4-hydroxy-3-methoxyphenyl)dodecan-3-one [a capsaicin/gingerol (Capsarol) analogue referred to as ZTX42] on NO production, inducible nitric oxide synthase (iNOS) activity and protein expression levels in a murine macrophage cell line, RAW 264.7. Both ZTX42 and [6]-DHP significantly inhibited lipopolysaccharide-induced NO production in a concentration-dependent manner, with an IC (50) of 1.45 +/- 0.03 microM and 7.24 +/- 0.22 microM, respectively (P < 0.05). Although both compounds partially inhibited the catalytic activity of iNOS, their inhibitory effect was predominantly due to attenuation of iNOS protein production. This occurred at the transcriptional level, since the gingerol compounds decreased LPS-induced IkappaB-alpha degradation, prevented nuclear translocation of NF-kappaB p65 and reduced NF-kappaB activity in a concentration-dependent manner. Taken together, these results show that ZTX42 and [6]-DHP suppress NO production in murine macrophages by partially inhibiting iNOS enzymatic activity and reducing iNOS protein production, via attenuation of NF-kappaB-mediated iNOS gene expression, providing a rationale for the anti-inflammatory activity reported for this class of compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / administration & dosage
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / therapeutic use
  • Capsaicin / analogs & derivatives
  • Catechols
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Fatty Alcohols / administration & dosage
  • Fatty Alcohols / pharmacology*
  • Fatty Alcohols / therapeutic use
  • Gene Expression Regulation / drug effects
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase Type II / genetics
  • Phytotherapy*
  • Zingiber officinale*


  • Anti-Inflammatory Agents
  • Catechols
  • Enzyme Inhibitors
  • Fatty Alcohols
  • Lipopolysaccharides
  • NF-kappa B
  • rac-2-hydroxy-1-(4-hydroxy-3-methoxyphenyl)dodecan-3-one
  • gingerol
  • Nitric Oxide Synthase Type II
  • Capsaicin