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CBD Derivative Could Help Treat Huntington’s Disease and Rare Skin Diseases, Study Suggests

By Alexander Beadle

Published: Nov 23, 2020   
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A research team have developed a new dual-action cannabidiol (CBD) derivative molecule that they claim is an even more potent antioxidant and anti-inflammatory than CBD alone.

The team, jointly led by researchers at the University of Dundee, Scotland, and the Universidad de Córdoba, Spain, believes that the new CBD derivative could someday be used to effectively treat rare skin diseases such as epidermolysis bullosa, or neurodegenerative diseases, including Huntington’s and Alzheimer’s disease.

Developing a new anti-inflammatory

In their previous research, the joint collaboration showed how CBD is able to induce the expression of heme oxygenase 1 – an enzyme with important antioxidant and anti-inflammatory properties – in the keratinocyte cells in the top layer of the skin by reducing the levels of a protein known as BACH1, which ordinarily suppresses the anti-inflammatory enzyme.

“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,” Professor Eduardo Muñoz, one of the two leading authors behind the new study, explained in a statement.

One of the other interesting pathways for reducing inflammation identified in this research was the activation of the NRF2 protein, which binds to antioxidant response elements (ARE) in its target genes and triggers the expression of heme oxygenase 1 and other antioxidants. Creating a molecule that is able to both suppress BACH1 and activate NRF2 could then provide a much more robust effect than CBD alone, as the cannabinoid is only a very weak NRF2 activator.

To do this, the team screened a library of semi-synthetic cannabidiol quinone derivatives in a reporter cell line that is known to respond well to NRF2 activation but not BACH1 inhibition, letting the researchers discriminate between the two activities. They identified the isomeric quinoids O-methyl para-cannabidiolquinone and O-methyl ortho-cannabidiolquinone as molecules of interest that could have good dual antioxidant properties.

Para-cannabidiolquinone protects against oxidative stress in cell models

Both of these cannabidiolquinones were validated experimentally by comparing them against known BACH1 inhibitors and NRF2 activators, confirming their effectiveness in suppressing BACH1 while both proved to be more potent than CBD at stimulating NRF2.

During this validation procedure, the researchers also discovered that the ortho-cannabidiolquinone isomer was significantly more toxic and less stable at room temperature than its para- equivalent. And so the researchers decided to proceed with a focus purely on the O-methyl para-cannabidiolquinone compound.

To assess whether O-methyl para-cannabidiolquinone might have beneficial therapeutic effects, the researchers exposed it to two cell lines acting as a cell model for Huntington’s disease, a neurodegenerative disease that presents high levels of oxidative stress and inflammation in the brain. The researchers found that O-methyl para-cannabidiolquinone clearly exhibits three distinct and important behaviors: as a direct antioxidant (similar to CBD), a BACH1 inhibitor, and an NRF2 activator.

In a further test using cell lines that had been treated with a neurotoxin capable of inducing significant oxidative damage, the CBD-derivative was able to significantly reduce the cytotoxicity of the neurotoxin, confirming its neuroprotective effect.

“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.

Towards a new class of CBD derivative drugs

The researchers also believe that this new CBD derivative could also be beneficial in treating inflammatory skin conditions, such as atopic dermatitis and epidermolysis bullosa. Just as CBD is able to produce an antioxidant and anti-inflammatory effect in the keratinocyte cells at the surface of the skin, the combined BACH1/NRF2 activity of O-methyl para-cannabidiolquinone could have an even more significant positive effect.

“[In the earlier study] we used skin cells as we were interested in the potential target of CBD in skin cells, which is relevant when CBD is used as a cream. In this new study, we also characterized the anti-inflammatory and antioxidant activity of the O-methyl cannabidiolquinone in skin cells, and thus its relevance in skincare is a given,” co-lead author Laureano de la Vega told Analytical Cannabis. De la Vega is a Cancer Research UK Fellow and group leader at the University of Dundee School of Medicine.

“As NRF2 and BACH1 are promising targets in some neurodegenerative diseases, we tested here whether the compound was active an in vitro model relevant to neurodegenerative disease conditions. The compound showed a protective effect against neuronal cell death, and thus the potential use of this compound for neurodegenerative diseases.”

The research team, working in collaboration with the companies Emerald Health Biotechnology, a developer of new medicines, and Innohealth Madrid, which specializes in natural dermo-cosmetics, are also collaborating on this research.

The group is currently looking to further optimize these molecules to improve their beneficial actions, with the future aim of progressing to animal studies where the real therapeutic potential of these drugs can be understood.

“Both NRF2 and BACH1 are key proteins involved in a variety of conditions, from cancer to neurodegenerative diseases. Our lab is studying whether some of these compounds, by targeting BACH1, might have some anticancer properties,” De la Vega added. “But these studies are very preliminary.”


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