These authors contributed equally to this work.
Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and Δ9-tetrahydrocannabinol in BV-2 microglial cells
Version of Record online: 23 MAR 2012
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society
British Journal of Pharmacology
Special Issue: Themed Section: Cannabinoids in Biology and Medicine, Part II. Guest Editors: Itai Bab and Steve Alexander
Volume 165, Issue 8, pages 2512–2528, April 2012
How to Cite
Juknat, A., Pietr, M., Kozela, E., Rimmerman, N., Levy, R., Coppola, G., Geschwind, D. and Vogel, Z. (2012), Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and Δ9-tetrahydrocannabinol in BV-2 microglial cells. British Journal of Pharmacology, 165: 2512–2528. doi: 10.1111/j.1476-5381.2011.01461.x
- Issue online: 23 MAR 2012
- Version of Record online: 23 MAR 2012
- Accepted manuscript online: 4 MAY 2011 05:24AM EST
- Received; 30 November 2010; Revised; 22 March 2011; Accepted; 13 April 2011
- gene expression;
- glutathione depletion;
- oxidative stress;
- nuclear factor-erythroid 2-related factor 2
BACKGROUND AND PURPOSE Apart from their effects on mood and reward, cannabinoids exert beneficial actions such as neuroprotection and attenuation of inflammation. The immunosuppressive activity of cannabinoids has been well established. However, the underlying mechanisms are largely unknown. We previously showed that the psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC) and the non-psychoactive cannabidiol (CBD) differ in their anti-inflammatory signalling pathways.
EXPERIMENTAL APPROACH To characterize the transcriptional effects of CBD and THC, we treated BV-2 microglial cells with these compounds and performed comparative microarray analysis using the Illumina MouseRef-8 BeadChip platform. Ingenuity Pathway Analysis was performed to identify functional subsets of genes and networks regulated by CBD and/or THC.
KEY RESULTS Overall, CBD altered the expression of many more genes; from the 1298 transcripts found to be differentially regulated by the treatments, 680 gene probe sets were up-regulated by CBD and 58 by THC, and 524 gene products were down-regulated by CBD and only 36 by THC. CBD-specific gene expression profile showed changes associated with oxidative stress and glutathione depletion, normally occurring under nutrient limiting conditions or proteasome inhibition and involving the GCN2/eIF2α/p8/ATF4/CHOP-TRIB3 pathway. Furthermore, CBD-stimulated genes were shown to be controlled by nuclear factors known to be involved in the regulation of stress response and inflammation, mainly via the (EpRE/ARE)-Nrf2/ATF4 system and the Nrf2/Hmox1 axis.
CONCLUSIONS AND IMPLICATIONS These observations indicated that CBD, but much less than THC, induced a cellular stress response in microglial cells and suggested that this effect could underlie its anti-inflammatory activity.
LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7