Abstract: Cannabinol (CBN), a cannabinoid derived from hashish, gives neuroprotective properties that would deal with neurological problems like Alzheimer’s, Parkinson’s, and traumatic mind accidents. Their examine particulars how CBN and its newly developed analogs stop mitochondrial dysfunction in neurons, a typical think about these illnesses.

The crew synthesized 4 CBN-based compounds, discovering one, specifically, to be extremely efficient in a fruit fly mannequin of mind harm. These findings not solely spotlight CBN’s therapeutic potential but additionally pave the way in which for future therapies geared toward mitigating mind cell loss of life in numerous neurological circumstances.

Key Information:

1. CBN and its derivatives present promise in defending neurons by enhancing mitochondrial operate, essential for stopping cell loss of life in neurological problems.
2. The Salk crew developed 4 new CBN analogs, with one exhibiting important efficacy in treating traumatic mind harm in fruit flies, indicating potential for human therapeutic use.
3. This analysis was supported by a number of foundations and NIH grants, underscoring its significance and potential impression on treating age-related neurological problems.

Supply: Salk Institute

One in each 10 people above the age of 65 develops an age-related neurological dysfunction like Alzheimer’s or Parkinson’s, but remedy choices stay sparse for this inhabitants.

Scientists have begun exploring whether or not cannabinoids — compounds derived from the hashish plant, like well-known THC (tetrahydrocannabinol) and CBD (cannabidiol) — might provide an answer.

A 3rd, lesser-known cannabinoid referred to as CBN (cannabinol) has lately piqued the curiosity of researchers, who’ve begun exploring the medical potential of the milder, much less psychoactive substance.

In a brand new examine, scientists on the Salk Institute assist clarify how CBN protects the mind towards growing older and neurodegeneration, then use their findings to develop potential therapeutics.

The researchers created 4 CBN-inspired compounds that have been extra neuroprotective than the usual CBN molecule — one in every of which was extremely efficient in treating traumatic mind harm in a Drosophila fruit fly mannequin.

The findings, revealed in Redox Biologyon March 29, 2024, counsel promise for CBN in treating neurological problems like traumatic mind harm, Alzheimer’s illness, and Parkinson’s illness, and likewise spotlight how additional research of CBN’s results on the mind might encourage the event of latest therapies for medical use.

“Not solely does CBN have neuroprotective properties, however its derivatives have the potential to turn into novel therapeutics for numerous neurological problems,” says Analysis Professor Pamela Maher, senior writer of the examine.

“We have been in a position to pinpoint the energetic teams in CBN which are doing that neuroprotection, then enhance them to create spinoff compounds which have higher neuroprotective potential and drug-like efficacy.”

Many neurological problems contain the loss of life of mind cells referred to as neurons, as a result of dysfunction of their power-generating mitochondria. CBN achieves its neuroprotective impact by stopping this mitochondrial dysfunction — however how precisely CBN does this, and whether or not scientists can enhance CBN’s neuroprotective skills, has remained unclear.

The Salk crew beforehand discovered that CBN was modulating a number of options of mitochondrial operate to guard neurons towards a type of cell loss of life referred to as oxytosis/ferroptosis.

After uncovering this mechanism of CBN’s neuroprotective exercise, they started making use of each tutorial and industrial drug discovery strategies to additional characterize and try to enhance that exercise.

First, they broke CBN into small fragments and noticed which of these fragments have been the simplest neuroprotectors by chemically analyzing the fragment’s properties. Second, they designed and constructed 4 novel CBN analogs — chemical look-alikes — wherein these fragments have been amplified, then moved them on to drug screening.

“We have been searching for CBN analogs that would get into the mind extra effectively, act extra rapidly, and produce a stronger neuroprotective impact than CBN itself,” says Zhibin Liang, first writer and postdoctoral researcher in Maher’s lab.

“The 4 CBN analogs we landed on had improved medicinal chemical properties, which was thrilling and actually essential to our purpose of utilizing them as therapeutics.”

To check the chemical medicinal properties of the 4 CBN analogs, the crew utilized them to mouse and human nerve cell cultures. After they initiated oxytosis/ferroptosis in three other ways, they discovered that every of the 4 analogs 1) have been in a position to shield the cells from dying, and a pair of) had related neuroprotective skills in comparison with common CBN.

The profitable analogs have been then put to the check in a Drosophila fruit fly mannequin of traumatic mind harm. One of many analogs, CP1, was particularly efficient in treating traumatic mind harm — producing the best survival charge after situation onset.

“Our findings assist reveal the therapeutic potential of CBN, in addition to the scientific alternative we now have to copy and refine its drug-like properties,” says Maher.

“May we in the future give this CBN analog to soccer gamers the day earlier than a giant recreation, or to automobile accident survivors as they arrive within the hospital? We’re excited to see how efficient these compounds is perhaps in defending the mind from additional harm.”

Sooner or later, the researchers will proceed to display screen and characterize these CBN analogs and refine their chemical designs. They will even start wanting extra intently at age-related neurodegeneration and adjustments in mind cells, significantly in mitochondria, asking how we are able to higher go well with these drug-like compounds to advertise mobile well being and forestall neuronal dysfunction with age.

Different authors embody David Soriano-Castell and Wolfgang Fischer of Salk; and Alec Candib and Kim Finley of the Shiley Bioscience Middle at San Diego State College.

Funding: The work was supported by the Paul F. Glenn Middle for Biology of Getting old Analysis on the Salk Institute, the Bundy Basis, the Shiley Basis, the Nationwide Institutes of Well being (R01AG067331, R21AG064287, R01AG069206, RF1AG061296, R21AG067334, NCI CCSG P30CA01495, NlA P30AG068635, S10OD021815), and the Helmsley Middle for Genomic Drugs.

About this CBD and neuropharmacology analysis information

Writer: Pamela Maher
Supply: Salk Institute
Contact: Pamela Maher – Salk Institute
Picture: The picture is credited to Neuroscience Information

Unique Analysis: Open entry.
“Fragment-based drug discovery and organic analysis of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological problems” by Pamela Maher et al. Redox Biology

Summary

Fragment-based drug discovery and organic analysis of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological problems

The oxytosis/ferroptosis regulated cell loss of life pathway is an rising area of analysis owing to its pathophysiological relevance to a variety of neurological problems, together with Alzheimer’s and Parkinson’s illnesses and traumatic mind harm.

Growing novel neurotherapeutics to inhibit oxytosis/ferroptosis gives thrilling alternatives for the remedy of those and different neurological illnesses.

Beforehand, we found cannabinol (CBN) as a novel, potent inhibitor of oxytosis/ferroptosis by focusing on mitochondria and modulating their operate in neuronal cells.

To additional elucidate which key pharmacophores and chemical house are important to the helpful results of CBN, we herein introduce a fragment-based drug discovery technique along with cell-based phenotypic screens utilizing oxytosis/ferroptosis to find out the structure-activity relationship of CBN.

The ensuing data led to the event of 4 new CBN analogs, CP1-CP4, that not solely protect the sub-micromolar efficiency of neuroprotection and mitochondria-modulating actions seen with CBN in neuronal cell fashions but additionally have higher druglike properties.

Furthermore, in comparison with CBN, the analog CP1 exhibits improved in vivo efficacy within the Drosophila mannequin of delicate traumatic mind harm. Collectively these research establish the important thing molecular scaffolds of cannabinoids that contribute to neuroprotection towards oxytosis/ferroptosis.

Additionally they spotlight the advantageous method of mixing in vitro cell-based assays and fast in vivo research utilizing Drosophila fashions for evaluating new therapeutic compounds.