Could Marijuana Substance Help Prevent or Delay Memory Impairment in the Aging Brain?

November 23, 2008

Science Daily/Ohio State University

Ohio State University scientists are finding that specific elements of marijuana can be good for the aging brain by reducing inflammation there and possibly even stimulating the formation of new brain cells.

Their research suggests that the development of a legal drug that contains certain properties similar to those in marijuana might help prevent or delay the onset of Alzheimer’s disease. Though the exact cause of Alzheimer’s remains unknown, chronic inflammation in the brain is believed to contribute to memory impairment.

Any new drug’s properties would resemble those of tetrahydrocannabinol, or THC, the main psychoactive substance in the cannabis plant, but would not share its high-producing effects. THC joins nicotine, alcohol and caffeine as agents that, in moderation, have shown some protection against inflammation in the brain that might translate to better memory late in life.

“It’s not that everything immoral is good for the brain. It’s just that there are some substances that millions of people for thousands of years have used in billions of doses, and we’re noticing there’s a little signal above all the noise,” said Gary Wenk, professor of psychology at Ohio State and principal investigator on the research.

Wenk’s work has already shown that a THC-like synthetic drug can improve memory in animals. Now his team is trying to find out exactly how it works in the brain.

The most recent research on rats indicates that at least three receptors in the brain are activated by the synthetic drug, which is similar to marijuana. These receptors are proteins within the brain’s endocannabinoid system, which is involved in memory as well as physiological processes associated with appetite, mood and pain response.

This research is also showing that receptors in this system can influence brain inflammation and the production of new neurons, or brain cells.

“When we’re young, we reproduce neurons and our memory works fine. When we age, the process slows down, so we have a decrease in new cell formation in normal aging. You need those cells to come back and help form new memories, and we found that this THC-like agent can influence creation of those cells,” said Yannick Marchalant, a study coauthor and research assistant professor of psychology at Ohio State.

Marchalant described the research in a poster presentation November 19 at the Society for Neuroscience meeting in Washington, D.C.

Knowing exactly how any of these compounds work in the brain can make it easier for drug designers to target specific systems with agents that will offer the most effective anti-aging benefits, said Wenk, who is also a professor of neuroscience and molecular virology, immunology and medical genetics.

“Could people smoke marijuana to prevent Alzheimer’s disease if the disease is in their family? We’re not saying that, but it might actually work. What we are saying is it appears that a safe, legal substance that mimics those important properties of marijuana can work on receptors in the brain to prevent memory impairments in aging. So that’s really hopeful,” Wenk said.

One thing is clear from the studies: Once memory impairment is evident, the treatment is not effective. Reducing inflammation and preserving or generating neurons must occur before the memory loss is obvious, Wenk said.

Marchalant led a study on old rats using the synthetic drug, called WIN-55212-2 (WIN), which is not used in humans because of its high potency to induce psychoactive effects.

The researchers used a pump under the skin to give the rats a constant dose of WIN for three weeks – a dose low enough to induce no psychoactive effects on the animals. A control group of rats received no intervention. In follow-up memory tests, in which rats were placed in a small swimming pool to determine how well they use visual cues to find a platform hidden under the surface of the water, the treated rats did better than the control rats in learning and remembering how to find the hidden platform.

“Old rats are not very good at that task. They can learn, but it takes them more time to find the platform. When we gave them the drug, it made them a little better at that task,” Marchalant said.

In some rats, Marchalant combined the WIN with compounds that are known to block specific receptors, which then offers hints at which receptors WIN is activating. The results indicated the WIN lowered the rats’ brain inflammation in the hippocampus by acting on what is called the TRPV1 receptor. The hippocampus is responsible for short-term memory.

With the same intervention technique, the researchers also determined that WIN acts on receptors known as CB1 and CB2, leading to the generation of new brain cells – a process known as neurogenesis. Those results led the scientists to speculate that the combination of lowered inflammation and neurogenesis is the reason the rats’ memory improved after treatment with WIN.

The researchers are continuing to study the endocannabinoid system’s role in regulating inflammation and neuron development. They are trying to zero in on the receptors that must be activated to produce the most benefits from any newly developed drug.

What they already know is THC alone isn’t the answer.

“The end goal is not to recommend the use of THC in humans to reduce Alzheimer’s,” Marchalant said. “We need to find exactly which receptors are most crucial, and ideally lead to the development of drugs that specifically activate those receptors. We hope a compound can be found that can target both inflammation and neurogenesis, which would be the most efficient way to produce the best effects.”

The National Institutes of Health supported this work.

https://www.sciencedaily.com/releases/2008/11/081119120141.htm

Cannabis Use, Effect and Potential Therapy for Alzheimer's, MS and Parkinson's

October 15, 2007

Science Daily/European College of Neuropsychopharmacology

Cannabis (marijuana) is the most widely produced plant-based illicit drug worldwide and the illegal drug most frequently used in Europe. Its use increased in almost all EU countries during the 1990s, in particular among young people, including school students. Cannabis use is highest among 15- to 24-year-olds, with lifetime prevalence ranging for most countries from 20--40% (EMCDDA 2006).

Recently there has been a new surge in the level of concern about potential social and health outcomes of cannabis use, although the available evidence still does not provide a clear-cut understanding of the issues. Intensive cannabis use is correlated with non-drug-specific mental problems, but the question of co-morbidity is intertwined with the questions of cause and effect (EMCDDA 2006). Prevention is of importance in adolescents, which is underlined by evidence that early-onset cannabis-users (pre- to mid-adolescence) have a significantly higher risk of developing drug problems, including dependence (Von Sydow et al., 2002; Chen et al., 2005).

The illegal status and wide-spread use of cannabis made basic and clinical cannabis research difficult in the past decades; on the other hand, it has stimulated efforts to identify the psychoactive constituents of cannabis. As a consequence, the endocannabinoid system was discovered, which was shown to be involved in most physiological systems -- the nervous, the cardiovascular, the reproductive, the immune system, to mention a few.

One of the main roles of endocannabinoids is neuroprotection, but over the last decade they have been found to affect a long list of processes, from anxiety, depression, cancer development, vasodilatation to bone formation and even pregnancy (Panikashvili et al., 2001; Pachter et al., 2006).

Cannabinoids and endocannabinoids are supposed to represent a medicinal treasure trove which waits to be discovered.

Raphael Mechoulam will tell the discovery story of the endocannabinoid system. His research has not only helped us to advance our understanding of cannabis use and its effects, but has also made key contributions with regard to understanding "neuroprotection," and has opened the door for the development of new drugs.

Endocannabinoid system

In the 1960s the constituent of the cannabis plant was discovered -- named tetrahydrocannabinol, or THC -- which causes the 'high' produced by it (Gaoni & Mechoulam, 1964). Thousands of publications have since appeared on THC. Today it is even used as a therapeutic drug against nausea and for enhancing appetite, and, surprisingly, has not become an illicit drug -- apparently cannabis users prefer the plant-based marijuana and hashish.

Two decades later it was found that THC binds to specific receptors in the brain and the periphery and this interaction initiates a cascade of biological processes leading to the well known marijuana effects. It was assumed that a cannabinoid receptor is not formed for the sake of a plant constituent (that by a strange quirk of nature binds to it), but for endogenous brain constituents and that these putative 'signaling' constituents together with the cannabinoid receptors are part of a new biochemical system in the human body, which may affect various physiological actions. 

In trying to identify these unknown putative signaling molecules, our research group in the 1990s was successful in isolating 2 such endogenous 'cannabinoid' components -- one from the brain, named anandamide (from the word ´ananda, meaning ´supreme joy´ in Sanscrit), and another one from the intestines named 2-arachidonoyl glycerol (2-AG) (Devane et al., 1992; Mechoulam et al., 1995).

Neuroprotection

The major endocannabinoid (2-AG) has been identified both in the central nervous system and in the periphery. Stressful stimuli -- traumatic brain injury (TBI) for example -- enhance brain 2-AG levels in mice. 2-AG, both of endogenous and exogenous origin, has been shown to be neuroprotective in closed head injury, ischemia and excitotoxicity in mice. These effects may derive from the ability of cannabinoids to act through a variety of biochemical mechanisms. 2-AG also helps repair the blood brain barrier after TBI. 

The endocannabinoids act via specific cannabinoid receptors, of which the CB1 receptors are most abundant in the central nervous system. Mice whose CB1 receptors are knocked out display slower functional recovery after TBI and do not respond to treatment with 2-AG. Over the last few years several groups have noted that CB2 receptors are also formed in the brain, particularly as a reaction to numerous neurological diseases, and are apparently activated by the endocannabinoids as a protective mechanism.

Through evolution the mammalian body has developed various systems to guard against damage that may be caused by external attacks. Thus, it has an immune system, whose main role is to protect against protein attacks (microbes, parasites for example) and to reduce the damage caused by them. Analogous biological protective systems have also been developed against non-protein attacks, although they are much less well known than the immune system. Over the last few years the research group of Esther Shohami in collaboration with our group showed that the endocannabinoid system, through various biological routes, lowers the damage caused by brain trauma. Thus, it helps to attenuate the brain edema and the neurological injuries caused by it (Panikashvili et al., 2001; Panikashvili et al., 2006).

Clinical importance

Furthermore it is assumed that the endocannabinoid system may be involved in the pathogenesis of hepatic encephalopathy, a neuropsychiatric syndrome induced by fulminant hepatic failure. Indeed in an animal model the brain levels of 2-AG were found to be elevated. Administration of 2-AG improved a neurological score, activity and cognitive function (Avraham et al., 2006). Activation of the CB2 receptor by a selective agonist also improved the neurological score. The authors concluded that the endocannabinoid system may play an important role in the pathogenesis of hepatic encephalopathy. 

Modulation of this system either by exogenous agonists specific for the CB2 receptors or possibly also by antagonists to the CB1 receptors may have therapeutic potential. The endocannabinoid system generally is involved in the protective reaction of the mammalian body to a long list of neurological diseases such as multiple sclerosis, Alzheimer's and Parkinson's disease. Thus, there is hope for novel therapeutic opportunities.

Numerous additional endocannabinoids -- especially various fatty acid ethanolamides and glycerol esters -- are known today and regarded as members of a large ´endocannabinoid family´. Endogenous cannabinoids, the cannabinoid receptors and various enzymes that are involved in their syntheses and degradations comprise the endocannabinoid system.

The endocannabinoid system acts as a guardian against various attacks on the mammalian body.

Conclusion

The above described research concerning the endocannabinoid-system is of importance in both basic science and in therapeutics:

·     The discovery of the cannabis plant active constituent has helped advance our understanding of cannabis use and its effects.

·     The discovery of the endocannabinoids has been of central importance in establishing the existence of a new biochemical system and its physiological roles -- in particular in neuroprotection.

·     These discoveries have opened the door for the development of novel types of drugs, such as THC for the treatment of nausea and for enhancing appetite in cachectic patients.

·     The endocannabinoid system is involved in the protective reaction of the mammalian body to a long list of neurological diseases such as multiple sclerosis, Alzheimer's and Parkinson's disease which raises hope for novel therapeutic opportunities for these diseases.

References

Avraham Y, Israeli E, Gabbay E, et al. Endocannabinoids affect neurological and cognitive function in thioacetamide-induced hepatic encephalopathy in mice. Neurobiology of Disease 2006;21:237-245

Chen CY, O´Brien MS, Anthony JC. Who becomes cannabis dependent soon after onset of use" Epidemiological evidence from the United States: 2000-2001. Drug and alcohol dependence 2005;79:11-22

Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992;258:1946-1949

[EMCDDA 2006] European Monitoring Centre for Drugs and Drug Addiction. The state of the drugs problem in Europe. Annual Report 2006 (http://www.emcdda.europa.eu)

Gaoni Y, Mechoulam R. Isolation, structure and partial synthesis of an active constituent of hashish. J Amer Chem Soc 1964;86:1646-1647

Journal Interview 85: Conversation with Raphael Mechoulam. Addiction 2007;102:887-893

Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 1995;50:83-90

Mechoulam R, Panikashvili D, Shohami E. Cannabinoids and brain injury. Trends Mol Med 2002;8:58-61

Pachter P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 2006;58:389-462

Panikashvili D, Simeonidou C, Ben-Shabat S, et al. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 2001;413:527-531

Panikashvili D, Shein NA, Mechoulam R, et al. The endocannabinoid 2-AG protects the blood brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines. Neurobiol Disease 2006;22:257-264

Von Sydow K, Lieb R, Pfister H, et al. What predicts incident use of cannabis and progression to abuse and dependence" A 4-year prospective examination of risk factors in a community sample of adolescents and young adults. Drug and alcohol dependence 2002;68:49-64

https://www.sciencedaily.com/releases/2007/10/071014163644.htm

Go for a run or eat chocolate: A choice dictated by the cannabinoid receptors

March 19, 2019

INSERM (Institut national de la santé et de la recherche médicale)

Physical inactivity is a common factor in lifestyle diseases -- and one that is often linked to the excessive consumption of fatty and/or sugary foods. The opposite scenario of excessive physical activity at the expense of caloric intake can also be harmful, as cases of anorexia nervosa illustrate. These data therefore point to the crucial need to research the neurobiological processes that control the respective motivations for exercise and food intake. A study by Inserm and CNRS researchers published on March 7, 2019 in JCI Insight reveals that the cannabinoid type 1 (CB1) receptors play an essential role in the choice between running and eating chocolatey food.

The authors of this paper had previously reported that the cannabinoid type-1 (CB1) receptors, present on several types of neurons, play a key role in performance during physical activity in mice. A conclusion based on the performances achieved by animals with free access to an exercise wheel -- a model in which it was not possible to distinguish the mechanism involved (motivation, pleasure...). Given that the motivation for a reward can only be estimated by measuring the efforts that the individual -- whether human or animal -- is prepared to make to get that reward, the researchers devised a model in which each access to the wheel was conditional on a prior effort. This involved the animal repeatedly introducing its snout into a recipient, an essential prerequisite for unlocking the wheel. After a training period during which the level of effort required to unlock the wheel remained the same, the mice were confronted with a test in which the effort required was gradually increased. When exposed to this test, the mice lacking CB1 receptors showed an 80 % deficit in the maximum effort they were prepared to make to unlock the wheel, and without a decrease in performance during their access to it. This finding indicates that the CB1 receptors play a major role in controlling motivation for exercise. The use of other genetically-modified mice also enabled the researchers to demonstrate that these CB1 receptors controlling motivation for exercise are located on GABAergic neurons.

The researchers then examined whether the CB1 receptors in the GABAergic neurons control the motivation for another reward: chocolatey food (like humans, mice love it even when they are otherwise well-fed). While the CB1 receptors also play a role in motivation for food -- albeit to a lesser extent than in motivation for exercise -- the CB1 receptors located on the GABAergic neurons are not implicated in the motivation for eating chocolatey food.

In our daily life, we are faced with an ongoing choice between various rewards. A fact which has encouraged the researchers to develop a model in which following a learning period the mice had the choice -- in return for the efforts described above -- between exercise and chocolatey food. The motivation for exercise was greater than that for chocolatey food, with the exception of the mice lacking CB1 -- whether generally or just on GABAergic neurons -- whose preference was for the food.

In addition to these findings indicating that the cannabinoid receptor is essential for the motivation for exercise, this study opens up avenues for researching the neurobiological mechanisms behind pathological increases in this motivation. One illustration is provided by anorexia nervosa which often combines the decreased motivation to eat with an increased motivation to exercise.

https://www.sciencedaily.com/releases/2019/03/190319121721.htm

Light-sensitive THC: Intoxicatingly light-sensitive

January 10, 2018

Science Daily/ETH Zurich

Chemists have synthesized several variants of THC, the active ingredient in cannabis. Its structure can be altered with light, and the researchers have used this to create a new tool that can be used to more effectively study the body's own cannabinoid system.

When many people hear the abbreviation THC (tetrahydrocannabinol), they immediately think of smoking marijuana and intoxication. But the substance is also of interest to medicine -- when given to people suffering from serious illnesses, it relieves muscle cramps, pain, loss of appetite and nausea.

THC works by binding to the corresponding cannabinoid-1 (CB1) receptors, which are located in the cell membrane and are present in large numbers in the central and peripheral nervous system. CB1 receptors play a major role in memory, motor coordination, mood and cognitive processes.

Receptors key to signal transmission

When a THC molecule binds to one of these CB1 receptors, it changes form, triggering a cascade of various signals inside the cell. However, it is still hard to study CB1 receptors and their manifold functions, because cannabinoids such as THC are highly lipophilic, so they frequently embed themselves in the membranes made of fat molecules in an uncontrolled manner. To be able to use THC or variants of it more precisely for pharmaceutical and medical applications, it is therefore important to gain a better understanding of CB1 receptors.

To study the diverse interactions between CB1 receptors and cannabinoids, a group of chemists headed by ETH professor Erick Carreira synthesised THC molecules. Their structure can be altered with light. The researchers published their findings in the latest issue of the Journal of the American Chemical Society.

Light-sensitive THC derivatives

The scientists synthesised four variants, or derivatives, of THC by attaching a light-sensitive "antenna" to the THC molecule. This antenna makes it possible to use light of a specific wavelength to precisely manipulate the altered molecule. Ultraviolet light changes the spatial structure of the antenna, and this change can be reversed again with blue light.

The researchers tested two of these derivatives in a living cell culture. The derivatives docked with CB1 receptors in the same way as naturally occurring THC. When the researchers irradiated the THC derivative with ultraviolet light, its structure altered just as the researchers expected, consequently activating the CB1 receptor. This triggers reactions such as the opening of the potassium ion channels located in the cell membrane, which causes potassium ions to flow out of the cell. The researchers were able to measure this with an electrode inserted into the cell.

When irradiated with blue light, the THC derivative returned to its original form, disabling the CB1 receptor as a result. The ion channels closed and the flow of potassium stopped. The researchers were able to activate and deactivate these processes using the corresponding coloured pulses of light.

A basis for light-controlled applications

"This work is our successful proof of principle: light-sensitive THC variants are a suitable tool for controlling and influencing CB1 receptors," says Michael Schafroth, a doctoral student with ETH professor Carreira and major contributor to the study. He added that they have now laid an important foundation for further projects that are already in progress; for example, another doctoral student in Carreira's group, Roman Sarott, is working on synthesising additional THC derivatives that react to long-wavelength red light. "Red light penetrates deeper into tissue than blue light," says Sarott. "If we want to study CB1 receptors in a living organism, we need molecules that are sensitive to red light."

In addition to the researchers from Carreira's group, leading scientists from New York University (NYU), the Indiana University Bloomington (IUB) and the University of Southern California (USC) as well as the Ludwig-Maximilian University in Munich were involved in the interdisciplinary project. The biological experiments were conducted by James Frank and Dirk Trauner.

A starting point for medicine

Many cultures have long known of the intoxicating and therapeutic effect of THC. The identification of THC eventually led to the discovery of the endocannabinoid system, which involves the body's native as well as exogenous substances in the cannabinoids class as well as their receptors in the body.

The pharmaceutical industry is also interested in gaining a better understanding of the endocannabinoid system so that it can better use specific components for pharmaceutical purposes. The system is considered a possible starting point for treatments for addiction, obesity, depression and even Alzheimer's and Parkinson's.

https://www.sciencedaily.com/releases/2018/01/180110112944.htm

Why Cannabis Stems Inflammation

July 22, 2008

Science Daily/ETH Zurich/Swiss Federal Institute of Technology

Cannabis has long been accredited with anti-inflammatory properties. Researchers, however, have now discovered that it is not only the familiar psychoactive substances that are responsible for this; a compound we take in every day in vegetable nutriment also plays a significant role.

People not only rate cannabis sativa L. highly because of its intoxicating effects; it has also long been used as a medicinal plant. Although the plant has been scrutinized for years, surprising new aspects keep cropping up. For example, researchers from ETH Zurich and Bonn University examined a component in the plant’s essential oil that until then had largely been ignored and found it to have remarkable phar- macological effects. The findings open up interesting perspectives, especially for the prevention and treatment of inflammations.

Completely different molecule structure

 The hemp plant contains over 450 different substances, only three of which are responsible for its intoxicating effect. They activate the two receptors in the body CB1 and CB2. Whilst the CB1 receptor in the central nervous system influences perception, the CB2 receptor in the tissue plays a crucial role in inhibiting inflammation. If the receptor is activated, the cell releases fewer pro-inflammatory signal substances, or cytokines. The scientists have now discovered that the substance beta-carophyllene, which composes between 12 and 35 percent of the cannabis plant’s essential oil, activates the CB2 receptor selectively.

Unlike the three psychoactive substances, however, beta-carophyllene does not latch onto the CB1 receptor and consequently does not trigger the intoxicating effect. “Due to the various effects of cannabis, we had suspected for quite some time that other substances could come into play besides the psychoactive ones”, explains Jürg Gertsch from the Institute of Pharmaceutical Sciences at ETH Zurich. “However, astonishingly we didn’t know what substances these were until now.”

Gertsch finds it remarkable that beta-carophyllene has a very different molecule structure to that of the classical cannabinoids. “This is presumably why no one realized that the substance can also activate the CB2 receptor.” The scientists were not only able to prove that beta-carophyllene binds with the CB2 receptor in vitro but also in animal tests, where they treated mice that were suffering from an inflammatory swelling on their paws with orally administered doses of the substance. The swelling declined in up to 70 percent of the animals, even for deep doses. For mice lacking the gene for the CB2 receptor, however, the substance did not make an impact.

Common substance

 The results are encouraging for the prevention or treatment of ailments in which the CB2 receptor plays a positive role. However, Gertsch explains that we are still very much in the early stages on that score. That said, the scientist can conceive that some day the compound will not only help heal certain forms of inflammation, but also be instrumental in treating chronic illnesses, such as liver cirrhosis, Morbus Crohn, osteoarthritis and arteriosclerosis. In all of these diseases, the CB2 receptor and the associated endocannabinoid system play a crucial role.

The beauty is that beta-carophyllene is not only found in cannabis but also often in plants as a whole and we consume the substance in our diet. The non-toxic compound, which incidentally has been used as a food additive for many years, can be found in spice plants like oregano, basil, cinnamon and black pepper. “Whether we have found a new link between the vegetable diet and the prevention of so-called lifestyle diseases in our study remains to be seen in future studies”, adds Gertsch.

https://www.sciencedaily.com/releases/2008/07/080720222549.htm