Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in beta-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-kappaB involvement

Neurosci Lett. 2006 May 15;399(1-2):91-5. doi: 10.1016/j.neulet.2006.01.047. Epub 2006 Feb 21.


In view of the pro-inflammatory scenario observed in Alzheimer's disease, in the recent years anti-inflammatory drugs have been proposed as potential therapeutic agents. We have previously shown that cannabidiol, the main non-psychotropic component from Cannabis sativa, possess a variegate combination of anti-oxidant and anti-apoptotic effects that protect PC12 cells from Abeta toxicity. In parallel, cannabidiol has been described to have anti-inflammatory properties in acute models of inflammation but the possible inhibitory effect of cannabidiol on iNOS protein expression and nitrite production in the nitrosative stress induced by Abeta in neuronal cell-line is un-investigated. Stimulation of differentiated PC12 cells with Abeta (1-42) (1 microg/mL) for 36 h caused a significant increase of nitrite production, compared to un-stimulated cells, that was inhibited in a concentration-dependent manner by both the non-selective iNOS inhibitor, L-NAME (0.3-30 microM), and, at higher extent, by the selective iNOS inhibitor SMT (0.3-30 microM). CBD (10(-6) to 10(-4) M) inhibited both nitrite production and iNOS protein expression induced by Abeta (1-42). Cannabidiol effect was mediated through the inhibition of phosphorylated form of p38 MAP kinase and transcription factor nuclear factor-kappaB activation in a concentration-dependent manner. The here reported data increases our knowledge about the possible neuroprotective mechanism of cannabidiol, highlighting the importance of this compound to inhibit beta-amyloid induced neurodegeneration, in view of its low toxicity in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / pharmacology*
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Cannabidiol / pharmacology*
  • Humans
  • Isothiuronium / analogs & derivatives
  • Isothiuronium / pharmacology
  • NF-kappa B / metabolism
  • NF-kappa B / physiology*
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Neuroprotective Agents / pharmacology*
  • Nitric Oxide / antagonists & inhibitors*
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase Type II / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II / biosynthesis
  • PC12 Cells
  • Peptide Fragments / pharmacology*
  • Phosphorylation
  • Rats
  • p38 Mitogen-Activated Protein Kinases / physiology*


  • Amyloid beta-Peptides
  • Anti-Inflammatory Agents
  • NF-kappa B
  • Neuroprotective Agents
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • Cannabidiol
  • Isothiuronium
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • p38 Mitogen-Activated Protein Kinases
  • S-methylisothiopseudouronium
  • NG-Nitroarginine Methyl Ester