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Cannabis reverses aging processes in the brain

Cannabis reverses aging processes in the brain
May 8, 2017 in Medicine & Health / Neuroscience

Memory performance decreases with increasing age. Cannabis can reverse these ageing processes in the brain. This was shown in mice by scientists at the University of Bonn with their colleagues at The Hebrew University of Jerusalem (Israel). Old animals were able to regress to the state of two-month-old mice with a prolonged low-dose treatment with a cannabis active ingredient. This opens up new options, for instance, when it comes to treating dementia. The results are now presented in the journal Nature Medicine.

Like any other organ, our brain ages. As a result, cognitive ability also decreases with increasing age. This can be noticed, for instance, in that it becomes more difficult to learn new things or devote attention to several things at the same time. This process is normal, but can also promote dementia. Researchers have long been looking for ways to slow down or even reverse this process.

Scientists at the University of Bonn and The Hebrew University of Jerusalem (Israel) have now achieved this in mice. These animals have a relatively short life expectancy in nature and display pronounced cognitive deficits even at twelve months of age. The researchers administered a small quantity of THC, the active ingredient in the hemp plant (cannabis), to mice aged two, twelve and 18 months over a period of four weeks.

Afterwards, they tested learning capacity and memory performance in the animals - including, for instance, orientation skills and the recognition of other mice. Mice who were only given a placebo displayed natural age-dependent learning and memory losses. In contrast, the cognitive functions of the animals treated with cannabis were just as good as the two-month-old control animals. "The treatment completely reversed the loss of performance in the old animals," reported Prof. Andreas Zimmer from the Institute of Molecular Psychiatry at the University of Bonn and member of the Cluster of Excellence ImmunoSensation.

Years of meticulous research
This treatment success is the result of years of meticulous research. First of all, the scientists discovered that the brain ages much faster when mice do not possess any functional receptors for THC. These cannabinoid 1 (CB1) receptors are proteins to which the substances dock and thus trigger a signal chain. CB1 is also the reason for the intoxicating effect of THC in cannabis products, such as hashish or marihuana, which accumulate at the receptor. THC imitates the effect of cannabinoids produced naturally in the body, which fulfil important functions in the brain. "With increasing age, the quantity of the cannabinoids naturally formed in the brain reduces," says Prof. Zimmer. "When the activity of the cannabinoid system declines, we find rapid ageing in the brain."

To discover precisely what effect the THC treatment has in old mice, the researchers examined the brain tissue and gene activity of the treated mice. The findings were surprising: the molecular signature no longer corresponded to that of old animals, but was instead very similar to that of young animals. The number of links between the nerve cells in the brain also increased again, which is an important prerequisite for learning ability. "It looked as though the THC treatment turned back the molecular clock," says Zimmer.

Next step: clinical trial on humans
A low dose of the administered THC was chosen so that there was no intoxicating effect in the mice. Cannabis products are already permitted as medications, for instance as pain relief. As a next step, the researchers want to conduct a clinical trial to investigate whether THC also reverses ageing processes in the brain in humans and can increase cognitive ability.
The North Rhine-Westphalia science minister Svenja Schulze appeared thrilled by the study: "The promotion of knowledge-led research is indispensable, as it is the breeding ground for all matters relating to application. Although there is a long path from mice to humans, I feel extremely positive about the prospect that THC could be used to treat dementia, for instance."

More information: Nature Medicine (2017). nature.com/articles/doi:10.1038/nm.4311 
"A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice" Andras Bilkei-Gorzo, Onder Albayram, Astrid Draffehn, Kirstin Michel, Anastasia Piyanova, Hannah Oppenheimer, Mona Dvir-Ginzberg, Ildiko Racz, Thomas Ulas, Sophie Imbeault, Itai Bob, Joachim L Schultze, Andreas Zimmer.

DETAILS: https://www.nature.com/nm/journal/vaop/ … 311-S1.pdf   
Provided by University of Bonn
"Cannabis reverses aging processes in the brain" May 8, 2017 https://medicalxpress.com/news/2017-05-cannabis-reverses-aging-brain.html

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Re: Cannabis reverses aging processes in the brain

January 26, 2022

update on:
Active ingredient in cannabis protects aging brain cells
Decades of research on medical cannabis has focused on the compounds THC and CBD in clinical applications. But less is known about the therapeutic properties of cannabinol (CBN). Now, a new study by Salk scientists shows how CBN can protect nerve cells from oxidative damage, a major pathway to cell death. The findings, published online January 6, 2022, in the journal Free Radical Biology and Medicine, suggest CBN has the potential for treating age-related neurodegenerative diseases, like Alzheimer's.
"We've found that cannabinol protects neurons from oxidative stress and cell death, two of the major contributors to Alzheimer's," says senior author Pamela Maher, a research professor and head of Salk's Cellular Neurobiology Laboratory. "This discovery could one day lead to the development of new therapeutics for treating this disease and other neurodegenerative disorders, like Parkinson's disease."
Derived from the cannabis plant, CBN is molecularly similar to THC, but is not psychoactive. It's also less heavily regulated by the FDA. Previous research by Maher's lab found that CBN had neuroprotective properties, but it wasn't clear how it worked. Now, this new study explains the mechanism through which CBN protects brain cells from damage and death.

Maher's team looked at the process of oxytosis, also called ferroptosis, which is thought to occur in the aging brain. Growing evidence suggests that oxytosis may be a cause of Alzheimer's disease. Oxytosis can be triggered by the gradual loss of an antioxidant called glutathione, causing neural cell damage and death via lipid oxidation. In the study, the scientists treated nerve cells with CBN, and then introduced an agent to stimulate oxidative damage.

They further found that the CBN worked by protecting mitochondria, the cell's powerhouses, within the neurons. In damaged cells, oxidation caused the mitochondria to curl up like donuts—a change that's also been seen in aging cells taken from the brains of people with Alzheimer's disease. Treating cells with CBN prevented the mitochondria from curling up and kept them functioning well.
To confirm the interaction between CBN and mitochondria, researchers then replicated the experiment in nerve cells that had the mitochondria removed. In these cells, CBN no longer demonstrated its protective effect.

"We were able to directly show that maintenance of mitochondrial function was specifically required for the protective effects of the compound," Maher said.
In another key finding, researchers showed that CBN did not activate cannabinoid receptors, which are required for cannabinoids to produce a psychoactive response. Thus, CBN therapeutics would work without causing the individual to become "high."

"CBN is not a controlled substance like THC, the psychotropic compound in cannabis, and evidence has shown that CBN is safe in animals and humans. And because CBN works independently of cannabinoid receptors, CBN could also work in a wide variety of cells with ample therapeutic potential," says first author Zhibin Liang, a postdoctoral fellow in the Maher lab.

In addition to Alzheimer's, the findings have implications for other neurodegenerative diseases, such as Parkinson's, which is also linked to glutathione loss. "Mitochondrial dysfunction is implicated in changes in various tissues, not just in the brain and aging, so the fact that this compound is able to maintain mitochondrial function suggests it could have more benefits beyond the context of Alzheimer's disease," Maher said.

Maher adds that the study shows the need for further research into CBN and other lesser-studied cannabinoids. As a next step, Maher's team is working to see if they can reproduce their results in a preclinical mouse model.

Paper: Zhibin Liang et al, Cannabinol inhibits oxytosis/ferroptosis by directly targeting mitochondria independently of cannabinoid receptors, Free Radical Biology and Medicine (2022). DOI: 10.1016/j.freeradbiomed.2022.01.001


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