Researchers have developed four CBN analogs (similar chemicals) derived from cannabis that have improved neuroprotective properties. These analogs show potential for treating neurological disorders such as Alzheimer’s, Parkinson’s, and traumatic brain injury. The study uncovers new information about CBN’s ability to protect the nervous system and highlights the importance of examining its analogs.
Approximately one in 10 people over the age of 65 experiences an age-related neurological disorder, such as Alzheimer’s or Parkinson’s. However, there are limited treatment options available for this demographic. Scientists are now looking into how…
Cannabinoids, which are compounds derived from the cannabis plant such as THC and CBD, may provide a solution. Researchers are now looking into the potential of a lesser-known cannabinoid called CBN, or cannabinol, which is milder and less psychoactive. In a recent study, scientists at the Salk Institute discovered how CBN can protect the brain from aging and neurodegeneration, and used their findings to develop potential treatments. The researchers developed four CBN-inspired compounds that showed more neuroprotective properties.e findings, which were published in Redox Biology on March 29, 2024, indicate that CBN may show potential in treating neurological disorders such as traumatic brain injury, Alzheimer’s disease, and Parkinson’s disease. The study also suggests that further research on CBN’s effects on the brain could lead to the development of new therapies for clinical use. The researchers identified derivatives of CBN that were more effective than the standard CBN molecule in treating traumatic brain injury in a Drosophila fruit fly model. This discovery highlights the potential for CBN and its derivatives to become novel therapeutics for various neurological disorders due to their neuroprotective properties.Research Professor Pamela Maher, the senior author of the study, explains, “We were able to identify the active groups in CBN that provide neuroprotection, and then enhance them to develop derivative compounds with greater neuroprotective ability and drug-like effectiveness.”
Many neurological disorders result in the death of neurons, which are brain cells, due to the malfunction of their mitochondria, which are responsible for generating power. CBN prevents this mitochondrial dysfunction, leading to its neuroprotective effect. However, the exact mechanism of how CBN achieves this and whether its neuroprotective abilities can be improved have remained unclear.
TheThe Salk team has previously discovered that CBN works to protect neurons from a type of cell death known as oxytosis/ferroptosis by modulating various aspects of mitochondrial function. Once they identified this mechanism of CBN’s neuroprotective activity, they began using both academic and industrial drug discovery methods to further study and enhance this activity.
First, they broke CBN down into smaller parts and analyzed the chemical properties of these fragments to determine which ones were the most effective at protecting neurons. Second, they created four new CBN analogs that closely resemble the original compound in order to further investigate its neuroprotective properties.
The researchers amplified those fragments and then moved them on to drug screening.
“We were seeking CBN analogs that could enter the brain more efficiently, act faster, and have a stronger neuroprotective effect than CBN itself,” explained Zhibin Liang, the first author and postdoctoral researcher in Maher’s lab. “The four CBN analogs we discovered had improved medicinal chemical properties, which was exciting and crucial to our goal of using them as therapeutics.”
To assess the medicinal properties of the four CBN analogs, the team tested them on mouse and human nerve cell cultures.
When they induced oxytosis/ferroptosis using three different methods, they discovered that all four analogs 1) were able to prevent cell death and 2) showed similar neuroprotective capabilities to regular CBN.
The effective analogs were then tested in a Drosophila fruit fly model of traumatic brain injury. One of the analogs, CP1, showed particularly promising results in treating traumatic brain injury, resulting in the highest survival rate after the onset of the condition.
“Our results highlight the therapeutic potential of CBN and the scientific opportunity to replicate and refine its drug-like properties.”Maher states that these CBN analogs show promise in protecting the brain from damage and could potentially be used for football players before a big game or for car accident survivors upon arrival at the hospital. The researchers will further study and refine the chemical designs of these compounds while also looking into age-related neurodegeneration and changes in brain cells, specifically in mitochondria. They are interested in how to better tailor these drug-like compounds to promote cellular health and prevent neuronal dysfunction.The study found that the gene responsible for regulating aging in worms is also involved in the process of aging in mammals. The research team included David Soriano-Castell and Wolfgang Fischer from Salk, as well as Alec Candib and Kim Finley from the Shiley Bioscience Center at San Diego State University. This work was supported by the Paul F. Glenn Center for Biology of Aging Research at the Salk Institute, the Bundy Foundation, the Shiley Foundation, the National Institutes of Health, and the Helmsley Center for Genomic Medicine. The journal reference for this study is Zhibin Liang, Ale.Candib, David Soriano-Castell, Wolfgang Fischer, Kim Finley, and Pamela Maher conducted a study on the fragment-based drug discovery and biological evaluation of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological disorders. The study was published in Redox Biology in 2024 and can be found at DOI: 10.1016/j.redox.2024.103138.