Unveiling Cannabinoid’s Potential for Treating Age-Related Brain Degeneration

Scientists at the Salk Institute observed the neuroprotective effects of cannabinol in fruit flies and discovered cannabinoid analogs that may prove to be promising future treatments for Parkinson's, Alzheimer's, and traumatic brain injury.

About 10% of people over 65 will experience an age-related neurological illness such as Parkinson's or Alzheimer's, but there are still few treatment options available for this demographic. Researchers are looking into the possibility that cannabinoids - compounds derived from the cannabis plant that are well-known for their effects, such as THC (tetrahydrocannabinol) and CBD (cannabidiol) - might be able to help.

Researchers have recently become interested in the clinical potential of CBN (cannabinol), a third, less well-known cannabinoid. CBN is a milder, less psychoactive substance.

In a recent study, scientists at the Salk Institute have contributed to the understanding of how CBN shields the brain from aging and neurodegeneration. They plan to use the results to guide the development of possible treatments. One of the four CBN-inspired compounds the researchers developed successfully treated traumatic brain injury in a Drosophila fruit fly model. These compounds were found to be more neuroprotective than the standard CBN molecule.

The research, which was published in Redox Biology, points to potential benefits for CBN in the treatment of neurological conditions such as Parkinson's disease, traumatic brain injury, and Alzheimer's disease. It also emphasizes how more research into the effects of CBN on the brain may lead to the creation of novel therapeutics for application in clinical settings.

Not only does CBN have neuroprotective properties, but its derivatives have the potential to become novel therapeutics for various neurological disorders. 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.”

Pamela Maher, Research Professor and Study Senior Author, Salk Institute

Numerous neurological conditions result in the death of neurons, which are brain cells, as a result of malfunctioning mitochondria, which produce energy. It is unclear how precisely CBN prevents this mitochondrial dysfunction and whether scientists can enhance CBN's neuroprotective properties, but this is how CBN achieves its neuroprotective effect.

Prior research by the Salk team discovered that CBN was controlling various aspects of mitochondrial function to shield neurons from oxytosis/ferroptosis, a type of cell death.

They started using both academic and commercial drug discovery techniques to further characterize and try to improve CBN's neuroprotective activity after they figured out its mechanism.

The team started by breaking up the CBN into smaller pieces and then used chemical analysis to determine which of those pieces worked best as neuroprotectors. Then, after amplifying those fragments, the team created four unique CBN analogs, or chemical lookalikes, and proceeded with 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. 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.”

Zhibin Liang, Study First Author and Postdoctoral Researcher, Salk Institute

The researchers used mouse and human nerve cell cultures to test the potential of the four CBN analogs as chemical medicines. Upon inducing oxytosis/ferroptosis in three distinct methods, they discovered that every one of the four analogs could 1) prevent the cells from perishing and 2) exhibit comparable neuroprotective properties to ordinary CBN.

The effective analogs were then tested in a traumatic brain injury model using Drosophila fruit flies. CP1, one of the analogs, demonstrated exceptional efficacy in treating traumatic brain injury, resulting in the highest rate of survival following 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. 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.”

Pamela Maher, Research Professor and Study Senior Author, Salk Institute

The scientists will keep screening, analyzing, and improving the chemical designs of these CBN analogs in the future. Additionally, they will start paying closer attention to changes in brain cells, especially in the mitochondria, and age-related neurodegeneration. They will be asking how one can tailor these drug-like compounds to support cellular health and prevent neuronal dysfunction as they age.

Source:
Journal reference:

Liang, Z., et al. (2024) Fragment-based drug discovery and biological evaluation of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological disorders. Redox Biology. doi.org/10.1016/j.redox.2024.103138

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