Cheating (Cell) Death

In a recent study, researchers from the Salk Institute for Biological Studies, San Diego, CA, US, examined the effect of cannabinol (CBN) on the process of oxytosis/ferroptosis – thought to occur in the aging brain. Though CBN is molecularly similar to THC, it’s not psychoactive and is less heavily regulated by the US FDA – making potential treatment options more accessible. To better understand the effects of CBN, the researchers treated nerve cells with the cannabinoid, and then introduced an agent causing oxidative damage (1). 

Their results showed CBN protected mitochondria within the neurons. In damaged cells, oxytosis/ferroptosis caused the mitochondria to curl up – an effect also seen in cells of people with Alzheimer’s disease (AD). However, CBN-treated mitochondria did not curl up and kept functioning well. To confirm the interplay between CBN and mitochondria, the team replicated the experiment in nerve cells that had their mitochondria removed. In these cells, CBN no longer demonstrated its protective effect. We spoke to Zhibin Liang, first author of the paper, about these findings.

What inspired this research?  
 

Over the past 20 years, our lab has been interested in the identification of potential AD drug candidates from natural products, particularly from medicinal plants. Cannabis has been used medicinally in humans for over 6000 years, but it has not been extensively studied as a potential source of drug candidates for neurodegenerative diseases. For decades, medical cannabis research has focused mainly on the major phytocannabinoids – namely, THC and CBD. 

As such, relatively little scientific knowledge has yet been curated for the minor but structurally diverse phytocannabinoids. Non-psychoactive phytocannabinoids have also not been fully explored as therapeutic options for age-associated neurodegenerative diseases. We decided to investigate those lesser-studied phytocannabinoids as potential treatments for AD and other age-related neurodegenerative disorders. 

Could you briefly summarize the main findings of your study? 
 

CBN proved itself to be a novel inhibitor of oxytosis/ferroptosis by directly targeting mitochondria and protecting neurons independently of cannabinoid CB1/CB2 receptor signaling. We also discovered that CBN activates endogenous antioxidant defenses and energy metabolism via AMP-activated protein kinase (AMPK) signaling in neurons. These findings suggest that CBN may be a novel mitochondrially-targeted agent to treat age-associated neurodegenerative disorders like AD, Parkinson’s, and Huntington’s diseases, as well as frontotemporal dementia, and amyotrophic lateral sclerosis. 

What are the main implications of your findings? 
 

Age-related neurodegenerative disorders, including AD, affect millions of people worldwide. To date, there are no drugs for any of these conditions that are disease-modifying in the sense that they slow down or reverse the progression of neurodegeneration. Aging leads to progressive and detrimental changes in the brain – and old age is the greatest risk factor for most neurodegenerative diseases. In addition, relatively little progress has been made towards preventing mitochondrial dysfunction. It is therefore critical to identify the functional changes that take place in the mitochondria with aging, to understand the root causes of age-related diseases, and then to translate the biology of aging into novel neurotherapeutics. 

Furthermore, our results indicate that CBN protects neurons from oxidative stress and cell death – two of the major contributors to AD. CBN also prevents the gradual loss of an endogenous antioxidant called glutathione; loss of glutathione results in neural cell damage and death via lipid oxidation. In addition to AD, our findings have implications for other neurodegenerative diseases, such as Parkinson’s, which is also linked to glutathione loss. Mitochondrial dysfunction is implicated in changes in various tissues (not just in the brain and aging), suggesting that CBN could have more benefits beyond the context of AD. 

Ultimately, we believe our discovery could one day lead to the development of new therapeutics for treating neurodegenerative disorders. Of course, more rigorous scientific investigations on CBN pharmacology will need to be done in the future. 

In the shorter term, we will aim to reproduce the results of CBN in a preclinical mouse model of AD and age-related dementia; the safety, pharmacokinetics, and efficacy profiles of CBN in preclinical animal models will be another clear focus.

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