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

Enhancing Activity of Marijuana-like Chemicals in Brain Helps Treat Parkinson's Symptoms in Mice

February 8, 2007

Science Daily/Stanford University Medical Center

Marijuana-like chemicals in the brain may point to a treatment for the debilitating condition of Parkinson's disease. In a study to be published in the Feb. 8 issue of Nature, researchers from the Stanford University School of Medicine report that endocannabinoids, naturally occurring chemicals found in the brain that are similar to the active compounds in marijuana and hashish, helped trigger a dramatic improvement in mice with a condition similar to Parkinson's.

"This study points to a potentially new kind of therapy for Parkinson's disease," said senior author Robert Malenka, MD, PhD, the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences. "Of course, it is a long, long way to go before this will be tested in humans, but nonetheless, we have identified a new way of potentially manipulating the circuits that are malfunctioning in this disease."

Malenka and postdoctoral scholar Anatol Kreitzer, PhD, the study's lead author, combined a drug already used to treat Parkinson's disease with an experimental compound that can boost the level of endocannabinoids in the brain. When they used the combination in mice with a condition like Parkinson's, the mice went from being frozen in place to moving around freely in 15 minutes. "They were basically normal," Kreitzer said.

But Kreitzer and Malenka cautioned that their findings don't mean smoking marijuana could be therapeutic for Parkinson's disease.

"It turns out the receptors for cannabinoids are all over the brain, but they are not always activated by the naturally occurring endocannabinoids," said Malenka. The treatment used on the mice involves enhancing the activity of the chemicals where they occur naturally in the brain. "That is a really important difference, and it is why we think our manipulation of the chemicals is really different from smoking marijuana."

The researchers began their study by focusing on a region of the brain known as the striatum. They were interested in that region because it has been implicated in a range of brain disorders, including Parkinson's, depression, obsessive-compulsive disorder and addiction.

The activity of neurons in the striatum relies on the chemical dopamine. A shortage of dopamine in the striatum can lead to Parkinson's disease, in which a person loses the ability to execute smooth motions, progressing to muscle rigidity, tremors and sometimes complete loss of movement. The condition affects 1.5 million Americans, according to the National Parkinson Foundation.

"It turns out that the striatum is much more complicated than imagined," said Malenka. The striatum consists of several different cell types that are virtually indistinguishable under the microscope. To uncover the individual contributions of the cell types, Malenka and Kreitzer used genetically modified mice in which the various cell types were labeled with a fluorescent protein that glows vivid green under a microscope. Having an unequivocal way to identify the cells allowed them to tease apart the functions of the different cell types.

Malenka's lab has long studied how the communication between different neurons is modified by experience and disease. In their examination of two types of mouse striatum cells, Kreitzer and Malenka found that a particular form of adaptation occurs in one cell type but not in the other.

Malenka said this discovery was exciting because no one had determined whether there were functional differences between the various cell types. Their study indicated that the two types of cells formed complementary circuits in the brain.

One of the circuits is thought to be involved in activating motion, while the other is thought to be involved in restraining unwanted movement. "These two circuits are critically involved in a push-pull to select the appropriate movement to perform and to inhibit the other," said Kreitzer.

Dopamine appears to modulate these two circuits in opposite ways. When dopamine is depleted, it is thought that the pathway responsible for inhibiting movement becomes overly activated - leading to the difficulty of initiating motion, the hallmark of Parkinson's disease.

Current treatment for Parkinson's includes drugs that stimulate or mimic dopamine. It turns out that the neurons Kreitzer identified as inhibiting motion had a type of dopamine receptor on them that the other cells didn't. The researchers tested a drug called quinpirole, which mimics dopamine, in mice with a condition similar to human Parkinson's disease, resulting in a small improvement in the mice.

"That was sort of expected," said Malenka. "The cool new finding came when we thought to use drugs that boost the activity of endocannabinoids." Based on prior knowledge of endocannabinoids and dopamine, they speculated that the two chemicals were working in concert to keep the inhibitory pathway in check.

When they added a drug that slows the enzymatic breakdown of endocannabinoids in the brain - URB597, being developed by Kadmus Pharmaceuticals in Irvine, Calif. - the results were striking.

"The dopamine drug alone did a little bit but it wasn't great, and the drug that targeted the enzyme that degrades endocannabinoids basically did nothing alone," Kreitzer said. "But when we gave the two together, the animals really improved dramatically."

This work was supported by a Ruth L. Kirchenstein Fellowship, the National Institutes of Health and the National Parkinson Foundation. Neither researcher has financial ties to Kadmus Pharmaceuticals.

https://www.sciencedaily.com/releases/2007/02/070207171915.htm