Cannabidiol, or CBD, is one of the most studied active chemicals — called cannabinoids — of the cannabis plant. CBD is devoid of the mind-altering effects linked with cannabis, and has antioxidant and anti-inflammatory properties that make it increasingly of interest as a therapy for several disorders, including EB.
But the mechanism of action underlying the therapeutic effects of CBD in skin diseases is unclear.
In the study “Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1,” published in the journal Redox Biology, researchers at the University of Cordoba, in Spain, and the University of Dundee, in Scotland, incubated the main cells of the top layer of the skin, called keratinocytes, with CBD for 24 hours and them compared them with untreated cells serving as controls.
The team looked at how the cell’s transcriptome — the entire set of messenger RNA molecules that carry the information needed to convert DNA into proteins — and proteome (all proteins) changed after treatment with CBD.
Their analysis revealed that CBD may promote the proliferation and maturation of keratinocytes, as well as pathways important for skin development. Such results were confirmed in mice.
One of the genes activated by CBD was HMOX1, which codes for a protein called heme oxygenase 1. This enzyme has antioxidant and anti-inflammatory properties in the skin. Further experiments showed that CBD led to the degradation of a protein called BACH1, which acts as a repressor of HMOX1.
Once the mechanism was clear, the researchers developed tweaked forms of CBD with enhanced antioxidant and anti-inflammatory effects.
“Once we described the whole working mechanism, we have continued our partnership, making modifications to the cannabidiol molecule in order to try to improve its properties that fight against skin diseases,” Eduardo Muñoz, a professor of immunology and the lead investigator of the research group at the University of Cordoba, said in a press release.
The team developed a derivative of CBD that not only blocks the action of BACH1 but also promotes the activity of the NRF2 protein, a master regulator of genes with antioxidant activity.
In the subsequent study “Isomeric O-methyl cannabidiolquinones with dual BACH1/NRF2 activity,” published in the same journal, these researchers showed that the new CBD derivative stabilized the NRF2 protein and induced HMOX1 activity. Cells models of Huntington’s disease, characterized by inflammation and oxidative stress, showed that this derivative of CBD has antioxidant properties and may also be beneficial in countering some effects of aging.
As a side note, oxidative stress is caused by an imbalance between the production of potentially harmful reactive oxygen species and antioxidant defenses.
“When combining the inhibition of BACH1 with the activation of NRF2, the result is a very potent antioxidant and anti-inflammatory response and better therapeutic effects,” Muñoz said.
Planned future research includes continuing to tweak the CBD-derived molecules, and to test them in animal models of skin diseases and other inflammatory disorders.
This work at the University of Cordoba led to the creation of Emerald Health Biotechnology and Innohealth Madrid, now part of Evonik Industries, which also collaborated in initial steps of the research.