One in 10 people over the age of 65 develops an age-related neurological disorder, such as Alzheimer’s or Parkinson’s, and therapeutic options remain scarce for these patients, so scientists have begun to explore whether cannabinoids, compounds derivatives of 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.
A new study by scientists at the Salk Institute helps explain how CBN protects the brain against aging and neurodegeneration and builds on its 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 injury in a Drosophila fruit fly model.
The results of the work have been published in Redox Biology and 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 highlights how additional studies on CBN’s effects on the brain could inspire the development of new therapies for clinical use.
“Not only does CBN have 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 carry out this neuroprotection and then improve them to create derivative compounds that have greater neuroprotective capacity and drug-like efficacy.”
Prevent neuronal dysfunction associated with aging
Many neurological disorders involve the death of brain cells called neurons, due to dysfunction of their energy-generating mitochondria. The neuroprotective effect of CBN occurs by preventing this mitochondrial dysfunction, but it is still unclear what the exact mechanism of action is and whether scientists will be able to improve the neuroprotective capabilities of CBN.
Salk’s team previously found 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 the neuroprotective activity of CBN, they began to apply both academic and industrial drug discovery methods to try to improve this activity.
First, they broke the CBN into small fragments and looked at which neuroprotectants were most effective 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 used them in the search for drugs.
“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,” said 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.”
“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 to protect the brain from further damage.”
To test the medicinal chemical properties of the four CBN analogues, 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 analogues was able to protect cells from death and, secondly, had similar neuroprotective abilities compared to normal CBN.
Successful analogues were then tested in a Drosophila fruit fly model of traumatic brain injury. One of the analogues – CP1 – was especially effective in treating traumatic brain injuries and produced 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 analogue 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 analyze and characterize these CBN analogs and refine their chemical designs. They will also begin to look in more detail at age-related neurodegeneration and changes in brain cells, particularly mitochondria, and examine how we can better tailor these drug-like compounds to promote cellular health and prevent neuronal dysfunction with age. .
