A compound found in cannabis may stave off a type of programmed cell death regularly seen in the neurons of people with Alzheimer’s disease, Parkinson’s disease, and other forms of dementia. Called cannabinol (CBN), the cannabinoid in question is not psychoactive and appears to keep aging brain cells alive by limiting oxidative stress within key cellular organelles. CBN has previously been found to have potent neuroprotective effects, but the mechanism underlying this property remains unknown. The researchers therefore chose to investigate the cannabinoid’s capacity to interrupt a form of cell death called oxytosis – aka ferroptosis – which is strongly associated with age-related neurodegeneration, detailing their discovery in the journal Free Radical Biology and Medicine. Oxytosis/ferroptosis occurs when cells’ supply of the antioxidant glutathione (GSH) is depleted, resulting in increased production of harmful reactive oxygen species (ROS) and a lethal influx of calcium ions across the cell membrane. The study authors triggered this process in hippocampal cells by administering high concentrations of glutamate, finding that this caused neurons to shrink and change shape. However, cells that were pre-treated with CBN remained healthy and undamaged after being incubated with glutamate, suggesting that the compound may somehow inhibit oxytosis/ferroptosis. Given that this type of cell death is known to generate a large increase in ROS in mitochondria – the organelles that generate cells’ energy – the study authors began to speculate that CBN may help to keep brain cells alive by protecting these key cellular structures. Further experiments revealed that, without this cannabinoid, the induction of oxytosis/ferroptosis caused mitochondria to curl up and stop functioning – but the addition of CBN prevented this morphological distortion. Crucially, the influx of calcium ions across mitochondrial membranes was also reduced by CBN, thus enabling these important organelles to continue operating normally. The experiment was repeated using brain cells engineered to lack mitochondria altogether, revealing that CBN was incapable of preventing oxytosis/ferroptosis in these neurons. This finding appears to confirm the pathway by which the cannabinoid protects aging brain cells, implying that the compound counteracts certain forms of programmed cell death by shielding mitochondria from oxidative damage. Commenting on these findings, study author Pamel Maher explained in a statement that “cannabinol protects neurons from oxidative stress and cell death, two of the major contributors to Alzheimer’s.” “This discovery could one day lead to the development of new therapeutics for treating this disease and other neurodegenerative disorders, like Parkinson’s disease,” she said. Importantly, the researchers found that CBN’s neuroprotective effects were maintained in brain cells that had been engineered to lack cannabinoid receptors, suggesting that it should work without causing people to become stoned. According to Maher, these observations could open the door to new treatment for a range of different disorders. “Mitochondrial dysfunction is implicated in changes in various tissues, not just in the brain and aging,” she said. “The fact that this compound is able to maintain mitochondrial function suggests it could have more benefits beyond the context of Alzheimer’s disease.” Source
