One in ten people over the age of 65 develops age-related neurological disorders such as Alzheimer’s disease and Parkinson’s disease, yet treatment options for this population remain sparse. Scientists have begun investigating whether cannabinoids, compounds derived from the cannabis plant such as the well-known THC (tetrahydrocannabinol) and CBD (cannabidiol), could provide a solution. His third, lesser-known cannabinoid, called CBN (cannabinol), has recently piqued the interest of researchers who have begun to explore the clinical potential of milder, less psychoactive substances.
In a new study, scientists at the Salk Institute explain how CBN protects the brain from aging and neurodegeneration, and use their findings to help develop potential treatments. Researchers have created four CBN-inspired compounds that are more neuroprotective than standard CBN molecules. One of them was highly effective in treating traumatic brain injuries caused by accidents. Drosophila Drosophila model.
The survey results are redox biology A March 29, 2024 paper suggests the potential of CBN in the treatment of neurological diseases such as traumatic brain injury, Alzheimer’s disease, and Parkinson’s disease, and further research into CBN’s effects on the brain is needed for clinical use. It highlights how it may impact the development of new treatments.
Not only does CBN have neuroprotective properties, but its derivatives may represent new treatments for various neurological diseases. We were able to identify the active groups within CBN that confer neuroprotection and refine them to create derivative compounds with better neuroprotective abilities and drug-like effects. ”
Pamela Maher, research professor and senior author of the study
Many neurological diseases involve the death of brain cells called neurons due to malfunction of the mitochondria that produce electricity. CBN exerts neuroprotective effects by preventing this mitochondrial dysfunction; how It remains unclear whether CBN does exactly this and whether scientists can improve CBN’s neuroprotective abilities.
The Salk team previously discovered that CBN modulates multiple features of mitochondrial function, protecting neurons from a type of cell death called oxytosis/ferroptosis. After elucidating this mechanism of CBN’s neuroprotective activity, they set out to apply both academic and industrial drug discovery techniques to further characterize and improve its activity.
First, they divided CBN into small fragments and by chemically analyzing the properties of the fragments, they observed which of those fragments were the most effective neuroprotective agents. Second, they designed and constructed four novel CBN analogs (chemical analogues), amplified their fragments, and transferred them to drug screening.
“We were looking for CBN analogs that could enter the brain more efficiently, act more quickly, and produce more potent neuroprotective effects than CBN itself,” said first author Maher. said Zhibin Liang, a postdoctoral researcher in the lab. “The four CBN analogs we arrived at had improved medicinal chemistry, which was exciting and critical to our goal of using them as therapeutics.”
To test the chemical efficacy of four CBN analogs, the research team applied them to cultures of mouse and human nerve cells. When oxytosis/ferroptosis was initiated in three different ways, each of the four analogs was shown to 1) be able to prevent cell death and 2) have similar neuroprotective abilities compared to regular CBN. got it.
Successful analogs were then tested in the following manner. Drosophila Drosophila model of traumatic brain injury. One of the analogues, CP1, was particularly effective in treating traumatic brain injury, resulting in the highest survival rates after symptom onset.
“Our findings help demonstrate the therapeutic potential of CBN. They also present scientific opportunities to reproduce and improve CBN’s drug-like properties,” says Maher. . “Would one day be able to administer this CBN analog to a soccer player on the eve of a big game, or to a car accident survivor when they arrive at the hospital? We hope that these compounds protect the brain from further damage. We’re excited to find out how effective it is in doing so.” ”
In the future, researchers plan to continue screening and characterizing these CBN analogs and refining their chemical designs. They’re also starting to look more closely at age-related neurodegeneration and changes in brain cells, particularly mitochondria, and are looking into using compounds like these drugs to promote cellular health and prevent age-related neurological dysfunction. We will look into how we can fit it properly.
Other authors include David Soriano Castel and Salk’s Wolfgang Fischer. Alec Candiv and Kim Finley of San Diego State University’s Shiley Bioscience Center.
This research was supported by the Paul F. Glenn Center for the Biology of Aging at the Salk Institute, the Bundy Foundation, the Shiley Foundation, the National Institutes of Health (R01AG067331, R21AG064287, R01AG069206, RF1AG061296, R21AG067334, NCI CCSG P30CA01495, NlA) . P30AG068635, S10OD021815) and Helmsley Center for Genomic Medicine.
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Reference magazines:
Liang, Z. et al. (2024). Fragment-based drug discovery and biological evaluation of novel cannabinol-based oxytosis/ferroptosis inhibitors for neurological diseases. redox biology. doi.org/10.1016/j.redox.2024.103138.
