Researchers from the Salk Institute created four CBN analogs with enhanced neuroprotective properties with potential for these neurological disorders as well as traumatic brain injury. Their findings published in Redox Biology revealed that one of the analogs was highly effective in treating traumatic brain injury as well as the novel aspects of the compound’s neuroprotective activity and demonstrated the potential of CBN’s effects on the brain that could lead to the development of new therapies.
“Not only does CBN have neuroprotective properties, but its derivatives have the potential to become novel therapeutics for various neurological disorders,” says Research Professor Pamela Maher, senior author of the study. “We were able to pinpoint the active groups in CBN that are doing that neuroprotection, then improve them to create derivative compounds that have greater neuroprotective ability and drug-like efficacy.”
Many neurological disorders involve the death of neurons due to the dysfunction of their mitochondria, CBN achieves a neuroprotective effect by preventing this mitochondria dysfunction, however, it is not clear exactly how it does this or whether the neuroprotective abilities can be improved upon.
According to the researchers, CBN modulates multiple features of mitochondrial function to protect neurons against oxytosis/ferroptosis cell death. After discovering this mechanism, the researchers began applying academic and industrial drug discovery methods to characterize and improve the activity. First CBN was broken into fragments to observe which were the most neuroprotective by chemically analyzing the fragment’s properties. After this four novel CBN analogs were designed with amplified neuroprotective properties which were moved to drug screening.
“We were looking for CBN analogs that could get into 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. “The four CBN analogs we landed on had improved medicinal chemical properties, which was exciting and really important to our goal of using them as therapeutics.”
The four enhanced CBN analogs were applied to mouse and human nerve cell cultures to test for medicinal properties, when oxytosis/ferroptosis was initiated in three different ways the researchers found that each of the analogs were able to protect the cells from dying, and they had similar neuroprotective abilities compared to regular CBN. The analogs were then tested in a Drosophila fruit fly model of traumatic brain injury (TBI), one was observed to be especially effective in treating TBI producing the highest survival rate after condition onset.
“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 as they arrive in the hospital? We’re excited to see how effective these compounds might be in protecting the brain from further damage.”
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https://www.salk.edu/news-release/protecting-brain-cells-with-cannabinol/
