title: Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and Δ9-tetrahydrocannabinol in BV-2 microglial cells.
abstract: OBJECTIVE
  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 Δ(9) -tetrahydrocannabinol (THC) and the non-psychoactive cannabidiol (CBD) differ in their anti-inflammatory signalling pathways.
  
  
  METHODS
  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.
  
  
  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
  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.
  
  
  BACKGROUND
  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.
authors.affiliation: The Dr. Miriam and Sheldon G. Adelson Center for the Biology of Addictive Diseases, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ana
authors.initials: A
authors.lastname: Juknat
authors.forename: Maciej
authors.initials: M
authors.lastname: Pietr
authors.forename: Ewa
authors.initials: E
authors.lastname: Kozela
authors.forename: Neta
authors.initials: N
authors.lastname: Rimmerman
authors.forename: Rivka
authors.initials: R
authors.lastname: Levy
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.forename: Daniel
authors.initials: D
authors.lastname: Geschwind
authors.forename: Zvi
authors.initials: Z
authors.lastname: Vogel
mesh_terms: D000818:Animals; D002185:Cannabidiol / Q000494:pharmacology*; D002460:Cell Line; D013759:Dronabinol / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005978:Glutathione / Q000235:genetics; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D002185:Cannabidiol; D013759:Dronabinol; D005978:Glutathione