One in 10 people over the age of 65 develops an age-related neurological disorder, such as Alzheimer’s or Parkinson’s, but treatment options remain scarce for this population. Scientists have begun to explore whether cannabinoids, compounds derived from the cannabis plant, such as the well-known THC (tetrahydrocannabinol) and CBD (cannabidiol), may offer a solution. A third, lesser-known cannabinoid called CBN (cannabinol) has recently sparked the interest of researchers, who have begun to explore the clinical potential of this milder, less psychoactive substance.
In a new study, Salk Institute scientists help explain how CBN protects the brain against aging and neurodegeneration and then use their findings to develop potential therapies. The researchers created four CBN-inspired compounds that were more neuroprotective than the standard CBN molecule, one of which was highly effective in treating traumatic brain injuries in a Drosophila fruit fly model.
The findings, published in Redox biologyon March 29, 2024, suggest that CBN shows promise in the treatment of neurological disorders such as traumatic brain injury, Alzheimer’s disease, and Parkinson’s disease, and also highlight how additional studies on CBN’s effects on the brain could inspire the development of new therapies for clinical use.
“CBN not only has neuroprotective properties, but its derivatives have the potential to become new therapies for various neurological disorders,” says research professor Pamela Maher, lead author of the study. “We were able to identify the active groups of CBN that perform that neuroprotection and then improve them to create derivative compounds that have greater neuroprotective capacity and drug-like efficacy.”
Many neurological disorders involve the death of brain cells called neurons, due to dysfunction of their energy-generating mitochondria. CBN achieves its neuroprotective effect by preventing this mitochondrial dysfunction, but as Exactly CBN does this, and it is still unclear whether scientists can improve CBN’s neuroprotective abilities.
Salk’s team previously discovered that CBN modulated multiple features of mitochondrial function to protect neurons against a form of cell death called oxytosis/ferroptosis. After discovering this mechanism of CBN’s neuroprotective activity, they began applying both academic and industrial drug discovery methods to further characterize and attempt to improve that activity.
First, they broke the CBN into small fragments and looked at which of those fragments were the most effective neuroprotectants by chemically analyzing the properties of the fragment. Secondly, they designed and built four new CBN analogues (chemical similarities) in which these fragments were amplified and then transferred them to drug detection.
“We were looking for CBN analogs that could enter the brain more efficiently, act more quickly, and produce a stronger neuroprotective effect than CBN itself,” says Zhibin Liang, first author and postdoctoral researcher in Maher’s lab. “All four CBN analogs we found had improved medicinal chemical properties, which was exciting and really important for our goal of using them as therapeutics.”
To test the medicinal chemical properties of the four CBN analogs, the team applied them to human and mouse nerve cell cultures. When they initiated oxytosis/ferroptosis in three different ways, they found that each of the four analogs 1) could protect cells from death and 2) had similar neuroprotective abilities compared to regular CBN.
The successful analogues were tested in a Drosophila Fruit fly model of traumatic brain injury. One of the analogs, CP1, was especially effective in treating traumatic brain injuries, producing the highest survival rate after the onset of the condition.
“Our findings help demonstrate the therapeutic potential of CBN, as well as the scientific opportunity we have to replicate and refine its drug-like properties,” says Maher. “Could we one day give this CBN analog to football players the day before a big game, or to car accident survivors when they arrive at the hospital? We are excited to see how effective these compounds could be in protecting the brain from major damage.”
In the future, researchers will continue to examine and characterize these CBN analogs and refine their chemical designs. They will also begin to look more closely at age-related neurodegeneration and changes in brain cells, particularly mitochondria, and ask how we can better tailor these drug-like compounds to promote cellular health and prevent neuronal dysfunction with age. .
Other authors include David Soriano-Castell and Wolfgang Fischer of Salk; and Alec Candib and Kim Finley of the Shiley Bioscience Center at San Diego State University.
The work was supported by the Paul F. Glenn Center for Research in 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 the Helmsley Center for Genomic Medicine.