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

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 PC 12 cells from A beta 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 NOS protein expression and nitrite production in the nitrosative stress induced by A beta in neuronal cell-line is un-investigated. Stimulation of differentiated PC12 cells with A beta (1-42) (1 mu g/mL) for 36h 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 mu M), and, at higher extent, by the selective iNOS inhibitor SMT (0.3-30 mu M). CBD (10(-6) to 10(-6) M) inhibited both nitrite production and iNOS protein expression induced by A beta (1-42). Cannabidiol effect was mediated through the inhibition of phosphorylated form of p38 MAP kinase and transcription factor nuclear factor-kappa B 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. (c) 2006 Elsevier Ireland Ltd. All rights reserved.