Antioxidant compound from soybeans may prevent marijuana-induced blood vessel damage
July 30, 2019
Science Daily/American Heart Association
Marijuana exposure damages cells of the inner lining of blood vessels throughout the heart and vascular system. In studies with human cells and arteries from mice, a compound found in soybeans blocked the damage and may have potential in preventing cardiovascular side effects of marijuana use.
In laboratory tests, a compound found in soybeans blocked damage to the lining of blood vessels in the heart and circulatory system and may someday provide a way to prevent the cardiovascular side effects of recreational and medical marijuana use, according to preliminary research presented at the American Heart Association's Basic Cardiovascular Sciences 2019 Scientific Sessions.
Marijuana is the most widely used illicit drug worldwide and is increasingly being made legal for recreational and medicinal purposes. However, there have been studies that link marijuana smoking to an increased risk of heart attack and stroke.
There can also be cardiovascular side effects, including changes in heart rate and blood pressure, when people take FDA-approved medications containing a synthetic version of delta-9-tetrahydrocannabinol (THC) -- the main compound in marijuana that gives the sensation of being high.
"These medications are prescribed to reduce the nausea and vomiting induced by chemotherapy and to increase appetite in certain people with acquired immune deficiency syndrome," said Tzu-Tan "Thomas" Wei, Ph.D., the study's lead author and assistant professor of pharmacology in the College of Medicine at National Taiwan University in Taipei City. "The goal of our studies is to investigate the mechanisms of marijuana-induced damage and discover new drugs to prevent those side effects."
The effects of THC occur after it binds to one of two cannabinoid receptors (CB1 and CB2) that are found throughout the brain and body and are also acted on by naturally occurring cannabinoids.
In the current study, the researchers used endothelial cells (like those that line blood vessels) derived from the stem cells of five healthy people. Exposing the cells to THC, they found that:
THC exposure induced inflammation and oxidative stress, which are known to affect the inner linings of blood vessels and are associated with the development of heart disease.
Lab techniques that block access to the CB1 receptor by THC eliminated the effects of THC exposure on endothelial cells.
Treatment with JW-1, an antioxidant compound found in soybeans, eliminated the effects of THC exposure.
In addition, the researchers used a laboratory technique called wire myography to examine the response of mouse arteries to THC, finding that JW-1 blocked THC's negative effects on the function of the inner lining.
An earlier attempt to gain health benefits from blocking the CB1 receptor proved problematic.
"Previously, a drug that blocked CB1 was approved in Europe for the treatment of obesity, but it had to be withdrawn because of severe psychiatric side effects," Wei said. "In contrast, as an antioxidant, JW-1 may have neuroprotective effects. Discovering a new way to protect blood vessels without psychiatric side effects would be clinically important with the rapid growth of cannabis use worldwide."
The researchers are currently extending their research by testing cells derived from regular marijuana users and those who smoke both cigarettes and marijuana. In addition, they are looking at the impact of THC along with the other main component of marijuana, cannabidiol.
"Meanwhile, if you have heart disease, talk to your doctor before you use marijuana or one of the synthetic THC-containing medications," Wei said. "Marijuana may cause more severe effects on the cardiovascular system in those with pre-existing heart disease."
https://www.sciencedaily.com/releases/2019/07/190730182430.htm
Vicious circle leads to loss of brain cells in old age
Researchers determine how dangerous inflammations in the brain are caused
Science Daily/August 31, 2018
University of Bonn
The so-called CB1 receptor is responsible for the intoxicating effect of cannabis. However, it appears to act also as a kind of "sensor" with which neurons measure and control the activity of certain immune cells in the brain. A recent study by the University of Bonn at least points in this direction. If the sensor fails, chronic inflammation may result -- probably the beginning of a dangerous vicious circle. The publication appears in the journal Frontiers in Molecular Neuroscience.
The activity of the so-called microglial cells plays an important role in brain aging. These cells are part of the brain's immune defense: For example, they detect and digest bacteria, but also eliminate diseased or defective nerve cells. They also use messenger substances to alert other defense cells and thus initiate a concerted campaign to protect the brain: an inflammation.
This protective mechanism has undesirable side effects; it can also cause damage to healthy brain tissue. Inflammations are therefore usually strictly controlled. "We know that so-called endocannabinoids play an important role in this," explains Dr. Andras Bilkei-Gorzo from the Institute of Molecular Psychiatry at the University of Bonn. "These are messenger substances produced by the body that act as a kind of brake signal: They prevent the inflammatory activity of the glial cells."
Endocannabinoids develop their effect by binding to special receptors. There are two different types, called CB1 and CB2. "However, microglial cells have virtually no CB1 and very low level of CB2 receptors," emphasizes Bilkei-Gorzo. "They are therefore deaf on the CB1 ear. And yet they react to the corresponding brake signals -- why this is the case, has been puzzling so far."
Neurons as "middlemen"
The scientists at the University of Bonn have now been able to shed light on this puzzle. Their findings indicate that the brake signals do not communicate directly with the glial cells, but via middlemen -- a certain group of neurons, because this group has a large number of CB1 receptors. "We have studied laboratory mice in which the receptor in these neurons was switched off," explains Bilkei-Gorzo. "The inflammatory activity of the microglial cells was permanently increased in these animals."
In contrast, in control mice with functional CB1 receptors, the brain's own defense forces were normally inactive. This only changed in the present of inflammatory stimulus. "Based on our results, we assume that CB1 receptors on neurons control the activity of microglial cells," said Bilkei-Gorzo. "However, we cannot yet say whether this is also the case in humans."
This is how it might work in mice: As soon as microglial cells detect a bacterial attack or neuronal damage, they switch to inflammation mode. They produce endocannabinoids, which activate the CB1 receptor of the neurons in their vicinity. This way, they inform the nerve cells about their presence and activity. The neurons may then be able to limit the immune response. The scientists were able to show that neurons similarly regulatory the other major glial cell type, the astroglial cells.
During ageing the production of cannabinoids declines reaching a low level in old individuals. This could lead to a kind of vicious circle, Bilkei-Gorzo suspects: "Since the neuronal CB1 receptors are no longer sufficiently activated, the glial cells are almost constantly in inflammatory mode. More regulatory neurons die as a result, so the immune response is less regulated and may become free-running."
It may be possible to break this vicious circle with drugs in the future. It is for instance hoped that cannabis will help slow the progression of dementia. Its ingredient, tetrahydrocannabinol (THC), is a powerful CB1 receptor activator -- even in low doses free from intoxicating effect. Last year, the researchers from Bonn and colleagues from Israel were able to demonstrate that cannabis can reverse the aging processes in the brains of mice. This result now suggest that an anti-inflammatory effect of THC may play a role in its positive effect on the ageing brain.
https://www.sciencedaily.com/releases/2018/08/180831130120.htm
Natural chemical helps brain adapt to stress
March 29, 2017
Science Daily/Vanderbilt University Medical Center
A natural signaling molecule that activates cannabinoid receptors in the brain plays a critical role in stress-resilience -- the ability to adapt to repeated and acute exposures to traumatic stress, according to researchers at Vanderbilt University Medical Center.
The findings in a mouse model could have broad implications for the potential treatment and prevention of mood and anxiety disorders, including major depression and post-traumatic stress disorder (PTSD), they reported in the journal Nature Communications.
"The study suggests that deficiencies in natural cannabinoids could result in a predisposition to developing PTSD and depression," said Sachin Patel, M.D., Ph.D., director of the Division of Addiction Psychiatry at Vanderbilt University School of Medicine and the paper's corresponding author.
"Boosting this signaling system could represent a new treatment approach for these stress-linked disorders," he said.
Patel, the James G. Blakemore Professor of Psychiatry, received a Presidential Early Career Award for Scientists and Engineers last year for his pioneering studies of the endocannabinoid family of signaling molecules that activate the CB1 and CB2 cannabinoid receptors in the brain.
Tetrahydrocannabinol (THC), the active compound in marijuana, binds the CB1 receptor, which may explain why relief of tension and anxiety is the most common reason cited by people who use marijuana chronically.
Patel and his colleagues previously have found CB1 receptors in the amygdala, a key emotional hub in the brain involved in regulating anxiety and the fight-or-flight response. They also showed in animal models that anxiety increases when the CB1 receptor is blocked by a drug or its gene is deleted.
More recently they reported anxiety-like and depressive behaviors in genetically modified mice that had an impaired ability to produce 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid. When the supply of 2-AG was increased by blocking an enzyme that normally breaks it down, the behaviors were reversed.
In the current study, the researchers tested the effects of increasing or depleting the supply of 2-AG in the amygdala in two populations of mice: one previously determined to be susceptible to the adverse consequences of acute stress, and the other which exhibited stress-resilience.
Augmenting the 2-AG supply increased the proportion of stress-resilient mice overall and promoted resilience in mice that were previously susceptible to stress, whereas depleting 2-AG rendered previously stress-resilient mice susceptible to developing anxiety-like behaviors after exposure to acute stress.
Taken together, these results suggest that 2-AG signaling through the CB1 receptor in the amygdala promotes resilience to the adverse effects of acute traumatic stress exposure, and support previous findings in animal models and humans suggesting that 2-AG deficiency could contribute to development of stress-related psychiatric disorders.
Marijuana use is highly cited by patients with PTSD as a way to control symptoms. Similarly, the Vanderbilt researchers found that THC promoted stress-resilience in previously susceptible mice.
However, marijuana use in psychiatric disorders has obvious drawbacks including possible addiction and cognitive side effects, among others. The Vanderbilt study suggests that increasing production of natural cannabinoids may be an alternative strategy to harness the therapeutic potential of this signaling system.
If further research finds that some people with stress-related mood and anxiety disorders have low levels of 2-AG, replenishing the supply of this endocannabinoid could represent a novel treatment approach and might enable some of them to stop using marijuana, the researchers concluded.
https://www.sciencedaily.com/releases/2017/03/170329140945.htm