Use of non-psychoactive cannabinoids in the treatment of neurodegenerative diseases

September 19, 2008

Science Daily/Complutense University of Madrid

Scientists at the Complutense University of Madrid (UCM) have studied the effects of a drug that reduces the progression of a disease similar to multiple sclerosis in animals. This discovery represents another step in the standing fight against the disease.

The research, published in the Journal of Biological Chemistry, aimed to study in depth the already known effects of lessening the symptoms and stopping the advance of multiple sclerosis that cannabinoids have, while developing a drug that would not have the psychoactive effects of the marijuana plant (Cannabis sativa). To achieve this, the scientists have focused their study on the role of the cannabinoids receptor CB2, present both in the immune system as well as in the defence-cells of the nervous system (microglial cells).

Multiple sclerosis is a neurodegenerative disease whose causes are not yet fully understood. It is known that the disease is produced by an autoimmune response where the defence-cells in the organism attack and destroy the nerve cells of the organism generating symptoms such as stiffness, twitching, progressive paralysis, etc.

The researchers managed by Professor Ismael Galve from the UCM, founded their conclusions on the role of the cannabinoids receptors in Experimental autoimmune encephalomyelitis, a disease that reproduces some of the processes and symptoms of multiple sclerosis. In the study it has been tested that administering a drug that activates receptor CB2 (but not CB1, responsible for the psychactive effects), the symptoms of the disease lessen and a reduction of 50% in nerve cell loss was perceived.

This research has introduced yet another novelty: The stimulation of the CB2 receptor not only reduces the excessive activation of brain cells in charge of the defence of the central nervous system, but it also reduces the supply of new defence-cells that travelling throughout the blood stream from bone marrow, would act as reinforcements for the defence-cells of the central nervous system.

According to Ismael Galve, the results are important because the drug is capable of acting in an already sick animal, reducing the symptoms and the brain cell loss. The obtained results, along with other predecessors confirm the role of endogenous cannabinoids in the origin of experimental autoimmune encephalomyelitis and its possible application to multiple sclerosis. Therefore the role of the CB2 receptor in the regulation and neuro-immune response supports the research currently being carried out on the possible use of cannabinoid drugs in the treatment of neurodegenerative diseases.

The research has been carried out by the department of biochemistry and molecular biology of the Complutense University of Madrid, in collaboration with the Neuroscience research Institute of Lyon in France and the pharmaceutical company Pharmos.

https://www.sciencedaily.com/releases/2008/09/080916154721.htm

Endocannabinoids -- The Brain's Cannabis -- Demonstrate Novel Modes of Action to Stress

July 20, 2005

Science Daily/American Physiological Society

Three separate research team reports -- one from Louisiana, one from Japan and one from Scotland -- are presenting independent research results pointing to involvement of endocannabinoids as a novel neural messenger in various stress-related situations with possible applications in eating, disease treatment and social behavior.

Tulane, LSU team on stress-related shutdown

The team from Tulane and Louisiana State Universities, led by Shi Di, found that in both physiological and psychological stress situations, stress hormones act on the brain to stimulate the release of endogenous cannabinoids from neurons in the hypothalamus, which act as a local messenger within the hypothalamus to shut down the neuroendocrine stress response.

One explanation for this hormone feedback regulation of the stress response might be to prepare the brain to mount another response in case of the onset of another possible stressor. The endogenous cannabinoids may serve to link the stress response with other neuroendocrine functions controlled by the hypothalamus, such as feeding.

Di says that the "actions of the endocannabinoids on the synaptic circuits that control the activity of the hypothalamic neurons serve to rapidly inhibit hormone secretion from the pituitary gland, providing a rapid negative feedback mechanism for the regulation of neuroendocrine function during stress."

Japanese team finds inhibition of excitatory and inhibitory synaptic transmission

In an in vitro study, a multi-center Japanese team led by Atsushi Soya focused on the supraoptic nucleus (SON) where vasopressin and oxytocin are synthesized. They found that a synthesized cannbinoid (CP55,940) inhibited both excitatory and inhibitory synaptic transmission and that a balanced input can produce sustained changes in neuronal activity without damage to neuronal homeostasis.

"Our next step is to investigate cannabinoids' effects in various stress conditions," Soya said. "Endocannabinoids may have possible involvement in stress-induced responses such as the changes of autonomic, endocrine and immune function."

Furthermore, Soya added, "cannabinoids are relevant to potential relief in such disease situations in the brain as multiple sclerosis and epilepsy, or feeding disorders. In these, their effects are similar to marijuana, except for the possible dangers of accidentally using the natural products at higher dosages."

Scottish team seeks social behavior answers

Nancy Sabatier of the University of Edinburgh, noted that "cannabis, or marijuana, is a drug that is widely abused because of the effects it can have on our mood and our social behavior. Cannabis works this way because it acts like substances that are produced inside our brains that are messengers between brain cells. Our work involves trying to understand what these substances, endocannabinoids, are for."

She said they are particularly interested in how endocannabinoids influence oxytocin cells in the brain, because because OT within the brain is involved in social behavior. "We have found that oxytocin cells produce endocannabinoids, and can release these to switch off other inputs to the oxytocin cells themselves. We are looking at what stimuli will cause oxytocin cells to release endocannabinoids to understand why this system might be important."

Sabatier noted that most related experiments are carried out in rats, "but we think that the basic ways in which these circuits work is very similar in all mammals. These brain circuits are very old in evolutionary terms, and they govern behaviors that are of fundamental importance to most species."

https://www.sciencedaily.com/releases/2005/07/050720065810.htm

How Do You Solve Relief -- Structure Of Pain-Modulating Enzyme Described By Scripps Scientists

Science Daily/November 29, 2002

The Scripps Research Institute

A group of researchers from The Scripps Research Institute (TSRI) have solved the structure of an enzyme that modulates central nervous system (CNS) functions such as pain perception, cognition, feeding, sleep, and locomotor activity.

The enzyme, described in the latest issue of the journal Science, is called fatty acid amide hydrolase (FAAH), and it breaks down certain fatty signaling molecules that reside in the lipid membranes of CNS cells. The TSRI group reports that FAAH modulates the action of these fatty signaling molecules through an unusual mechanism of action whereby it scoops them out of the cell membranes and chews them up.

"I envision that if someone could make a specific inhibitor to FAAH, you could, in principal, get pain relief without any of the side effects," says Benjamin Cravatt, one of the paper’s lead authors and an investigator in TSRI's Department of Cell Biology, Department of Chemistry, and The Skaggs Institute for Chemical Biology.

"As soon as we had the view of the active site, we knew FAAH could be used to make lead clinical candidates," adds Raymond Stevens, who is a professor in the Department of Molecular Biology and Chemistry at TSRI and the other lead author on the paper. "The deep pocket with well-defined cavities provides the guidance to take the currently available tight binding inhibitors and improve on their specificity and pharmakokinetic properties."

Pain Management and FAAH

Easing pain is practically synonymous with practicing medicine, and since before the days of Hippocrates, doctors have sought the best ways of doing this--looking for compounds that not only ease pain, but do so as fast, effectively, and lastingly as possible--and without any unwanted side effects.

Every analgesic, from opiates to hypnotism to electroshocks to balms, have side effects, and therein lies the rub: whether relieving the pain or the side effects is more pressing.

One compound that has been hotly debated in the last 10 years is delta-9-tetrahydrocannabinol (THC), the active ingredient in marijuana. The reason THC works is that it mimics the action of natural cannabinoids that the body produces in signaling cascades in response to a peripheral pain stimulus. THC binds to "CB-1" receptors on cells on the rostral ventromedial medulla, a pain-modulating center of the brain, decreasing sensitivity to pain.

Unfortunately, the receptors that THC bind to are also widely expressed in other parts of the brain, such as in the memory and information-processing centers of the hippocampus. Binding to nerve cells of the hippocampus and other cells elsewhere in the body, THC creates a range of side effects as it activates CB-1 mediated signaling--including distorted perception, difficulty in problem-solving, loss of coordination, and increased heart rate and blood pressure, anxiety, and panic attacks.

The challenge posed by THC and other cannabinoids is to find a way to use them to produce effective, long-lasting relief from pain without the deleterious side effects. Now Cravatt and Stevens think they know just how to do that.

The solution, as they see it, is to increase the efficacy of the natural, endogenous cannabinoids ("endocannabinoids") the body produces to modulate pain sensations.

"When you feel pain, you release endocannabinoids [which provide some natural pain relief]," says Cravatt. "Then the amplitude and duration of their activity are regulated by how fast they are broken down."

In particular, the body releases an endogenous cannabinoid called anandamide, a name derived from the Sanskrit word meaning "internal bliss." When the body senses pain, anandamide binds to CB-1 and nullifies pain by blocking the signaling. However, this effect is weak and short-lived as FAAH quickly metabolizes the anandamide--the compound has a half-life of only a few minutes in vivo.

In some ways, THC is superior to anandamide as a pain reliever because it is not as readily metabolized by FAAH. But THC goes on to suppress cannabinoid receptor activity all over the body. This, coupled with the fact that it is a controlled substance, makes THC an unattractive target for developing therapeutics.

FAAH is much more attractive target for pain therapy because by inhibiting FAAH, you would increase the longevity of anandamide molecules--preventing their breakdown and allowing them to continue providing some natural pain relief.

The structure that Cravatt, Stevens, and their TSRI colleagues solved should form a template for designing specific inhibitors that control the action of FAAH when the body is sensing pain and releasing anandamide.

The research article, "Structural Adaptations in a Membrane Enzyme that Terminates Endocannabinoid Signaling" is authored by Michael H. Bracey, Michael A. Hanson, Kim R. Masuda, Raymond C. Stevens, and Benjamin F. Cravatt, and appears in the November 29, 2002 issue of the journal Science.

The research was funded by the National Institute on Drug Abuse, the Searle Scholars Program, The Skaggs Institute for Chemical Biology, a National Research Service Award, and a Jabinson graduate fellowship.

https://www.sciencedaily.com/releases/2002/11/021127072047.htm