Pubdate: Thu, 24 Feb 2005
Source: Jerusalem Post (Israel)
Copyright: 2005 The Jerusalem Post
Contact: http://info.jpost.com/C002/Services/Feedback/editors.html
Website: http://www.jpost.com/
Details: http://www.mapinc.org/media/516
Author: Judy Siegel-Itzkovich
Bookmark: http://www.mapinc.org/mmj.htm (Cannabis - Medicinal)

STUDY: MARIJUANA SLOWS ALZHEIMER'S DECLINE

New Spanish and Israeli research shows that a synthetic analogue of the active component of marijuana can reduce the inflammation and prevent the mental decline associated with Alzheimer's disease.  Although it was conducted on human brain tissue in the lab and in a rat model -- but not in living humans -- the research is regarded as a major step not only in understanding how the brain reacts to Alzheimer's disease, but also in helping to develop novel drugs for Alzheimer's and even Parkinson's disease.

Prof.  Raphael Mechoulam, a medicinal chemistry expert who discovered marijuana's active component ( called THC ), conducted the study with researchers at the Cajal Institute and Complutense University in Madrid, led by Maria de Ceballos.  The study appears in Wednesday's issue of The Journal of Neuroscience, which is published by the Society for Neuroscience, an organization of more than 36,000 basic scientists and clinicians who study the brain and nervous system.

To show the preventive effects of cannabinoids on Alzheimer's disease, the team first compared the brain tissue of patients who died from Alzheimer's disease with that of healthy people who had died at a similar age.  They looked closely at cannabinoid receptors CB1 and CB2 - proteins to which cannabinoids bind, allowing their effects to be felt - and atmicroglia, which activate the brain s immune response.  Micro-glia collect near plaques and, when active, cause inflammation.  The researchers found a dramatically reduced functioning of cannabinoid receptors in diseased brain tissue, meaning that patients had lost the capacity to experience cannabinoids' protective effects.

In addition, the researchers showed that cannabinoids prevented cognitive decline through rat experiments.  They injected either amyloid ( which leads to cognitive decline ) that had been allowed to aggregate or control proteins into the brains of rats for one week.  Other rats were injected with a cannabinoid and either amyloid or a control protein.  After two months, the researchers trained the rats over five days to find a platform hidden underwater.  Rats treated with the control protein - with or without cannabinoids - and those treated with the amyloid protein and cannabinoid were able to find the platform.  Rats treated with amyloid protein alone did not learn how to find the platform.

Meshoullam said that the discovery was important, since most drugs given for neurodegenerative diseases like Alzheimer's and Parkinson's are work merely against symptoms and not the cause and essence of the neurodegeneration.  It is not necessary to smoke marijuana to conduct trials, but to use the synthetic versions of the active ingredient, he told The Jerusalem Post.

Clinical trials have not yet been scheduled or a request made for approval.  It is very complicated and expensive to run clinical trials, he said, but he hoped they would be carried out due to the massive threat to human health of Alzheimer's and other neurodegenerative disorders.

The researchers found that the presence of amyloid protein in the rats' brains activated immune cells.  Rats that received the control protein alone or cannabinoid and a control protein did not show activation of microglia.  Using cell cultures, the investigators confirmed that cannabinoids counteracted the activation of microglia and thus reduced inflammation. 

These findings that cannabinoids work both to prevent inflammation and to protect the brain may set the stage for their use as a therapeutic approach for Alzheimer's disease, de Ceballos said.  The scientists will now focus their efforts on targeting one of the two main cannabinoid receptors that is not involved in producing the psychotropic effects, or high, from marijuana.

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The compound may protect the brain

The active ingredient in marijuana may stall decline from Alzheimer's disease, research suggests.

Scientists showed a synthetic version of the compound may reduce inflammation associated with Alzheimer's and thus help to prevent mental decline.

They hope the cannabinoid may be used to developed new drug therapies.

The research, by Madrid's Complutense University and the Cajal Institute, is published in the Journal of Neuroscience.

We would warn the public against taking marijuana as a way of preventing Alzheimer's Dr Susanne Sorensen

They looked closely at brain cell receptors to which cannabinoids bind, allowing their effects to be felt.

They also studied structures called microglia, which activate the brain's immune response.

Microglia collect near the plaque deposits associated with Alzheimer's disease and, when active, cause inflammation.

The researchers found a dramatically reduced functioning of cannabinoid receptors in diseased brain tissue.

This was an indication that patients had lost the capacity to experience cannabinoids' protective effects.

The next step was to test the effect of cannabinoids on rats injected with the amyloid protein that forms Alzheimer's plaques.

Those animals who were also given a dose of a cannabinoid performed much better in tests of their mental functioning.

The researchers found that the presence of amyloid protein in the rats' brains activated immune cells.

However, rats that also received the cannabinoid showed no sign of microglia activation.

Using cell cultures, the researchers confirmed that cannabinoids counteracted the activation of microglia and thus reduced inflammation.

Drug target

Researcher Dr Maria de Ceballos said: "These findings that cannabinoids work both to prevent inflammation and to protect the brain may set the stage for their use as a therapeutic approach for Alzheimer's disease."

Dr Susanne Sorensen, head of research at the Alzheimer's Society, said: "This is important research because it provides another piece of the jigsaw puzzle on the workings of the brain.

"There is no cure for Alzheimer's disease, so the identification of another target for drug development is extremely welcome.

"The Alzheimer's Society looks forward to seeing further research being carried out on cannabinoid receptors as drug targets for Alzheimer's disease but would warn the public against taking marijuana as a way of preventing Alzheimer's.

"It is now generally recognised that as well as providing a 'high', long-term use of marijuana can also lead to depression in many individuals."

Different receptors

Harriet Millward, of the Alzheimer's Research Trust, said there were two main types of cannabinoid receptor, CR1 and CR2.

"It is CR1 that produces most of the effects of marijuana, including the harmful ones.

"If it is possible to make drugs that act only on CR2, as suggested by the authors of this study, they might mimic the positive effects of cannabinoids without the damaging ones of marijuana.

"However, this is a fairly new field of research and producing such selective drugs is not an easy task.

"There is also no evidence yet that cannabinoid-based drugs can slow the decline in human Alzheimer's patients."

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Neurobiology of Disease

Neuroprotection Mediated by Blockade of Microglial Activation

Neurodegeneration Group, Cajal Institute, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain, and Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain

Received Sep 9, 2004; revised December 28, 2004; accepted December 30, 2004.

Discovery Could Lead to More Effective Treatments

LA JOLLA, CA, August 9, 2006 - Scientists at The Scripps Research Institute have found that the active ingredient in marijuana, tetrahydrocannabinol or THC, inhibits the formation of amyloid plaque, the primary pathological marker for Alzheimer's disease. In fact, the study said, THC is "a considerably superior inhibitor of [amyloid plaque] aggregation" to several currently approved drugs for treating the disease.

The study was published online August 9 in the journal Molecular Pharmaceutics, a publication of the American Chemical Society.

According to the new Scripps Research study, which used both computer modeling and biochemical assays, THC inhibits the enzyme acetylcholinesterase (AChE), which acts as a "molecular chaperone" to accelerate the formation of amyloid plaque in the brains of Alzheimer victims. Although experts disagree on whether the presence of beta-amyloid plaques in those areas critical to memory and cognition is a symptom or cause, it remains a significant hallmark of the disease. With its strong inhibitory abilities, the study said, THC "may provide an improved therapeutic for Alzheimer's disease" that would treat "both the symptoms and progression" of the disease.

"While we are certainly not advocating the use of illegal drugs, these findings offer convincing evidence that THC possesses remarkable inhibitory qualities, especially when compared to AChE inhibitors currently available to patients," said Kim Janda, Ph.D., who is Ely R. Callaway, Jr. Professor of Chemistry at Scripps Research, a member of The Skaggs Institute for Chemical Biology, and director of the Worm Institute of Research and Medicine. "In a test against propidium, one of the most effective inhibitors reported to date, THC blocked AChE-induced aggregation completely, while the propidium did not. Although our study is far from final, it does show that there is a previously unrecognized molecular mechanism through which THC may directly affect the progression of Alzheimer's disease."

As the new study points out, any new treatment that could halt or even slow the progression of Alzheimer's disease would have a major impact on the quality of life for patients, as well as reducing the staggering health care costs associated with the disease.

Alzheimer's disease is the leading cause of dementia among the elderly, and the numbers are growing. The Alzheimer's Association estimates 4.5 million Americans have the disease, a figure that could reach as high as 16 million by 2050. A survey by the National Center for Health Statistics noted that half of all nursing home residents have Alzheimer's disease or a related disorder. The costs of caring for Alzheimer's patients are at least $100 billion annually, according to the National Institute on Aging.

Over the last two decades, the causes of Alzheimer's disease have been clarified through extensive biochemical and neurobiological studies, leading to an assortment of possible therapeutic strategies including interference with beta amyloid metabolism, the focus of the Scripps Research study.

The cholinergic system - the nerve cell system in the brain that uses acetylcholine (Ach) as a neurotransmitter - is the most dramatic of the neurotransmitter systems affected by Alzheimer's disease. Levels of acetylcholine, which was first identified in 1914, are abnormally low in the brains of Alzheimer's patients. Currently, there are four FDA-approved drugs that treat the symptoms of Alzheimer's disease by inhibiting the active site of acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine.

"When we investigated the power of THC to inhibit the aggregation of beta-amyloid," Janda said, "we found that THC was a very effective inhibitor of acetylcholinesterase. In addition to propidium, we also found that THC was considerably more effective than two of the approved drugs for Alzheimer's disease treatment, donepezil (Aricept ®) and tacrine (Cognex ®), which reduced amyloid aggregation by only 22 percent and 7 percent, respectively, at twice the concentration used in our studies. Our results are conclusive enough to warrant further investigation."

Other authors of the study, titled "A Molecular Link Between the Active Component of Marijuana and Alzheimer's Disease Pathology," include Lisa M. Eubanks, Claude J. Rogers, and Tobin J. Dickerson of The Scripps Research Institute, the Skaggs Institute for Chemical Biology, and the Worm Institute for Research and Medicine; and Albert E. Beuscher IV, George F. Koob, and Arthur J. Olson of The Scripps Research Institute.

The study was supported by the Skaggs Institute for Chemical Biology at Scripps Research and the National Institutes of Health.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus in 2009.

For more information contact:
Office of Communications
10550 North Torrey Pines Road
La Jolla, California 92037
[email protected]

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                       IACM-Bulletin of 06 March 2005

• Science: Cannabinoids reduce the progression of Alzheimer's disease in animals
• UK/USA: GW Pharmaceuticals accelerates plans to introduce Sativex in the USA
• News in brief
• A glimpse @ the past

Science: Cannabinoids reduce the progression of Alzheimer's disease in animals

Research by scientists of Madrid's Complutense University and the Cajal Institute published in the Journal of Neuroscience has demonstrated that cannabinoids can reduce pathological processes associated with Alzheimer's disease. Researchers hope that cannabinoids may be used to develop new drug therapies against the disease.

They first compared the brain tissue of patients who died from Alzheimer's disease with that of healthy people who had died at a similar age. The researchers found a dramatically reduced functioning of cannabinoid receptors in diseased brain tissue and markers of microglia activation. Microglia activate the brain's immune response and are found near the plaque deposits associated with Alzheimer's disease. When active, microglia cause inflammation. Nerve cells with cannabinoid-1 receptors (CB1), present in high numbers in control subjects, were greatly reduced in areas of microglial activation.

In a second step rats were injected with amyloid-beta peptide. This protein plays an important role in Alzheimer's disease, since increased brain levels of amyloid-beta are supposed to result in aggregation of this protein to form plaques. Animals who also received different cannabinoids performed better in tests of their mental functioning. Analyses showed that cannabinoids had prevented microglial activation and thus had reduced inflammation. These effects were also mediated by cannabinoids that only bind to CB2 receptors.

Researchers concluded: "Our results indicate that cannabinoid receptors are important in the pathology of AD and that cannabinoids succeed in preventing the neurodegenerative process occurring in the disease."

British researchers, who published their work in the journal Sub-Cellular Biochemistry, found that phosphorylation of amyloid-beta increased the neurotoxicity of this protein. And they demonstrated that cannabinoids prevented these damaging effects of phosphorylated amyloid-beta on nerve cells.

(Sources: Ramirez BG, et al. Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci 2005;25(8):1904-13; Milton NG. Phosphorylated amyloid-beta: the toxic intermediate in alzheimer's disease neurodegeneration. Subcell Biochem 2005;38:381-402; BBC News of 22 February 2005)

UK/USA: GW Pharmaceuticals accelerates plans to introduce Sativex in the USA

The British company GW Pharmaceuticals said on 28 February it was accelerating plans to introduce its cannabis-based medicines into the United States. GW said it had engaged the U.S.-based Apjohn Group, a 10-member group of former major U.S. pharmaceutical company executives with extensive experience in clinical development, regulatory affairs and public policy.

GW's Sativex has won qualified approval in Canada for the treatment of neuropathic pain in multiple sclerosis in December 2004, but approval in Great Britain for the treatment of spasticity in multiple sclerosis has been repeatedly delayed. Sativex is an under-the-tongue cannabis spray containing equal amounts of THC and CBD.

(Source: Reuters of 28 February 2005)

News in brief

Canada: Tax relief for medical cannabis
Canadians will get tax relief to buy medical cannabis under the federal budget proposed by finance minister Ralph Goodale. Marijuana bought for medical purposes from Health Canada or a designated grower will be eligible for tax relief after the annual medical expenses exceed 3 per cent of net income or 1,844 Canadian dollars. (Source: Toronto Star of 24 February 2005)

Austria: New research centre
A new research centre for plant derived drugs will be founded in Innsbruck. The main focuses of Bionorica Research will be the investigation of plant derived airway therapeutics and the investigation of cannabis products for medical purposes. A subsidiary company of Bionorica in Germany, Delta 9 Pharma, already produces the cannabis compound dronabinol (THC) for medical uses. (Source: Der Standard of 28 February 2005)

USA: New Mexico
The state Senate of New Mexico has approved three separate bills that would allow the medical use of cannabis, but it is unclear whether the House of Representatives will support them. Under one of the measures, the cannabis would be grown at licensed, secure facilities and then distributed to patients who were registered to possess and smoke it. An alternative bill requires the medical marijuana to be manufactured by a drug company. The third bill the Senate endorsed would allow the use of marijuana only topically, such as in an ointment. (Source: Associated Press of 2 March 2005)

Australia: Australian Capital Territory
Changes of the drug laws of the Australian Capital Territory (ACT), one of the Australian states, came into effect on 6 March. They reduce the number of cannabis plants that can be cultivated without being charged with a criminal offence from five to two plants. The criminal law allows a person to posses up to 25 grams of dried cannabis for personal use. (Source: Government of ACT of 1 March 2005, www.cmd.act.gov.au)

A molecular link between the active component of marijuana and Alzheimer's disease pathology. [Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
Mol Pharm 2006 Nov-Dec; 3(6):773-7.

Alzheimer's disease is the leading cause of dementia among the elderly, and with the ever-increasing size of this population, cases of Alzheimer's disease are expected to triple over the next 50 years. Consequently, the development of treatments that slow or halt the disease progression have become imperative to both improve the quality of life for patients and reduce the health care costs attributable to Alzheimer's disease. Here, we demonstrate that the active component of marijuana, Delta9-tetrahydrocannabinol (THC), competitively inhibits the enzyme acetylcholinesterase (AChE) as well as prevents AChE-induced amyloid beta-peptide (Abeta) aggregation, the key pathological marker of Alzheimer's disease. Computational modeling of the THC-AChE interaction revealed that THC binds in the peripheral anionic site of AChE, the critical region involved in amyloidgenesis. Compared to currently approved drugs prescribed for the treatment of Alzheimer's disease, THC is a considerably superior inhibitor of Abeta aggregation, and this study provides a previously unrecognized molecular mechanism through which cannabinoid molecules may directly impact the progression of this debilitating disease.

Scientists at The Scripps Research Institute in La Jolla, California, have found that THC inhibits the formation of amyloid plaque, the primary pathological marker for Alzheimer's disease. The study to be published in Molecular Pharmaceutics says, THC is "a considerably superior inhibitor of [amyloid plaque] aggregation" to several currently approved drugs for treating the disease.

According to the new experimental study THC inhibits a protein, which acts as a accelerator of the formation of amyloid plaque in the brains of Alzheimer victims. Although experts disagree on whether the presence of beta-amyloid plaques in those areas critical to memory and cognition is a symptom or cause, it remains a significant hallmark of the disease. With its strong inhibitory abilities, the study said, THC "may provide an improved therapeutic for Alzheimer's disease" that would treat "both the symptoms and progression" of the disease.

(Source: Press release by the Scripps Research Institute of 9 August 2006, www.scripps.edu/news/press/080906.html)

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Neurobiol Aging. 2008 Dec;29(12):1894-901. Epub 2007 Jun 11.

Marchalant Y, Cerbai F, Brothers HM, Wenk GL.

Department of Psychology, Psychology Building, Ohio State University, Columbus, OH 43210, USA. [email protected]

PMID: 17561311 [PubMed - indexed for MEDLINE]PMCID: PMC2586121Free PMC Article

Images from this publication.See all images (4) Free text

Figure 1

Water maze performance. During day 2 and 3, young rats receiving the 0.5 mg/kg WIN dose (open circle) performed significantly worse than rats in the other two young groups (open triangle and open square) († p<0.05). On day 4, the young rats receiving the 2 mg/kg WIN dose (open square) performed sign...

Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats

Neurobiol Aging. Author manuscript; available in PMC 2009 December 1.;29(12):1894-1901.

Figure 2

(A.) Activated microglia in the CA3 region. Note the diminution of activated microglia cells in this region of rats treated with 2 mg/kg/day of WIN 55212-2 (f), as compared to the normal aged rats (d). Scale bar: 100µm (B.) Density of activated microglial cells in different areas of interest. Microg...

Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats

Neurobiol Aging. Author manuscript; available in PMC 2009 December 1.;29(12):1894-1901.

Figure 3

Protein expression of CB1 receptors in the hippocampus. No changes in protein expression were found between groups for CB1 receptors in the hippocampus of rats.

Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats

Neurobiol Aging. Author manuscript; available in PMC 2009 December 1.;29(12):1894-1901.

 

 

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Figure 4

Immunoreactivity (IR) of CB1 in the CA3 region of the hippocampus. All scale bars: 50 µm. (A) CB1-IR (red) do not co-localized with OX-6-IR (green), as magnified in (a). (B) CB1-IR (green) and NeuN-IR (red) do co-localize, as magnified in (b). (C) CB1-IR (green) and GFAP-IR (red) do not co-localize ...

Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats

Neurobiol Aging. Author manuscript; available in PMC 2009 December 1.;29(12):1894-1901.

Abstract

Cannabinoids have been found to have antioxidant properties, unrelated to NMDA receptor antagonism. This new found property makes cannabinoids useful in the treatment and prophylaxis of wide variety of oxidation associated diseases, such as ischemic, age-related, inflammatory and autoimmune diseases.

The cannabinoids are found to have particular application as neuroprotectants, for example in limiting neurological damage following ischemic insults, such as stroke and trauma, or in the treatment of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and HIV dementia. Nonpsychoactive cannabinoids, such as cannabidoil, are particularly advantageous to use because they avoid toxicity that is encountered with psychoactive cannabinoids at high doses useful in the method of the present invention. A particular disclosed class of cannabinoids useful as neuroprotective antioxidants is formula (I) wherein the R group is independently selected from the group consisting of H, CH3, and COCH3. ##STR1##

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• Ottersen et al., "The Crystal and Molecular Structure of Cannabidiol," Acta Chem. Scand. B 31, 9:807-812 (1977)
• Cunha et al., "Chronic Administration of Cannabidiol to Healthy Volunteers and Epileptic Patients¹," Pharmacology, 21:175-185 (1980)
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• Colasanti et al., "Ocular Hypotension, Ocular Toxicity,a nd Neurotoxicity in Response to Marihuana Extract and Cannabidiol," Gen Pharm., Pergamon Press Ltd., 15(6):479-484 (1984)
• Colasanti et al., "Intraocular Pressure, Ocular Toxicity and Neurotoxicity after Administration of Cannabinol or Cannabigerol," Exp. Eye Res., Academic Press Inc., 39:251-259 (1984)
• Volfe et al., "Cannabinoids Block Release of Serotonin from Platelets Induced by Plasma frm Migraine Patients," Int. J. Clin. Pharm. Res., Bioscience Ediprint Inc., 4:243-246 (1985)
• Agurell et al., "Pharmacokinetics and Metabolism of Ɗ¹ -Tetrahydrocannabinol and Other Cannabinoids with Emphasis on Man*," Pharmacological Reviews, 38(1):21-43 (1986)
• Karler et al., "Different Cannabinoids Exhibit Different Pharmacological and Toxicological Properties,"NIDA Res. Monogr., 79:96-107 (1987)
• Samara et al., "Pharmacokinetics of Cannabidiol in Dogs," Drug Metabolism and Disposition, 16(3):469-472 (1988)
• Choi, "Glutamate Neurotoxicity and Diseases of the Nervous System," Neuron, Cell Press, 1:623-634 (1988)
• Eshhar et al., "Neuroprotective and Antioxidant Activities of HU-211, A Novel NMDA Receptor Antagonist," European Journal of Pharmacology, 283:19-29 (1995)
• Skaper et al., "The ALIAmide Palmitoylethanolamide and Cannabinoids, but not Anandamide, are Protective in a Delayed Postglutamate Paradigm of Excitotoxic Death in Cerebellar Granule Neurons," Neurobiology, Proc. Natl. Acad. Sci. USA, 93:3984-3989 (1996)
• Alonso et al., "Simple Synthesis of 5-Substituted Resorcinols: A Revisited Family of Interesting Bioactive Molecules," J. Org. Chem., American Chemical Society, 62(2):417-421 (1997)
• Combes et al. "A Simple Synthesis of the Natural 2,5-Dialkylresorcinol Free Radical Scavenger Antioxidant: Resorstation," Synthetic Communications, Marcel Dekker, Inc., 27(21):3769-3778 (1997)
• Shohami et al., "Oxidative Stress in Closed-Head Injury: Brain Antioxidant Capacity as an Indicator of Functional Outcome," Journal of Cerebral Blood Flow and Metabolism, Lippincott-Raven Publishers, 17(10):1007-1019 (1997)
• Zurier et al., "Dimethylheptyl-THC-11 OIC Acid," Arthritis & Rheumatism, 41(1):163-170 (1998)
• Hampson et al., "Dual Effects of Anandamide on NMDA Receptor-Mediated Responses and Neurotransmission," Journal of Neurochemistry, Lippincott-Raven Publishers, 70(2):671-676 (1998)
• Hampson et al., "Cannabidiol and (-)Ɗ⁹ -tetrahydrocannabiono are Neuroprotective Antioxidants," Medical Sciences, Proc. Natl. Acad. Sci. USA, 8268-8273 (1998)

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The more research they do, the more evidence Ohio State University scientists find 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.

The 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 Wednesday (11/19) 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.

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Tolón RM, Núñez E, Pazos MR, Benito C, Castillo AI, Martínez-Orgado JA, Romero J.

Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, 28922 Alcorcón, Madrid, Spain.

PMID: 19505450 [PubMed - indexed for MEDLINE]

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Two new studies point to a wonderful way to ward off Alzheimer's disease and other forms of age-related memory los

A large-scale study released this week showed that the herb gingko biloba has no effect in preventing dementia or Alzheimer’s disease. But alternative medicine aficionados may find hope in a new research touting the bennies of another "herb" in preserving memory.

Scientists from Ohio State University report that marijuana, contrary to the conventional wisdom,  may help ward off Alzheimer's and keep recall sharp. Their findings, released today at the Society for Neuroscience meeting in Washington D.C.:  chemical components  of marijuana reduce inflammation and stimulate the production of new brain cells, thereby enhancing memory.

The team suggested that a  drug could be formulated that would resemble tetrahydroannibol, or THC, the psychoactive  ingredient in pot sans making the user high. But the research  may ultimately drive those who fear impending dementia to roll their own solution to the problem.

Study co-author Gary Wenk, a professor of psychology, had already devised a preliminary version of a THC-like synthetic drug that improves memory in lab animals. His team at the meeting said that it works by activating at least three receptors in the brain targeted by THC—proteins on the surface of nerve cells  that then trigger cellular processes resulting in reduced inflammation and production of new brain cells that can boost recall. Understanding how the compounds work  may pave the way for a pharmaceutical company to prepare its own  med for human clinical trials.

The researchers ducked the obvious question of whether it might be simpler, faster and cheaper to simply light up a joint. “Could people smoke marijuana to prevent Alzheimer’s disease if the disease is in their family?" Wenk said in a statement. "We’re not saying that, but it might actually work.”

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