Parkinson's Disease

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Marijuana-Like Brain Chemicals Ease Parkinson's Symptoms in Mice

Forbes
02.07.07, 12:00 AM ET

WEDNESDAY, Feb. 7 (HealthDay News) -- Manipulation of brain molecules similar to those found in marijuana provided dramatic relief of Parkinson's-like symptoms in mice, researchers report.

"This might be a target for treatment that could cure the motor deficits seen in Parkinson's disease," said lead researcher Anatol Kreitzer, whose team published the findings in the Feb. 8 issue of Nature.

Kreitzer emphasized two points, however -- that a lot of work must be done before human trials can begin, and that the study results do not support smoking marijuana as a way to help Parkinson's patients.

The study did involve cannabinoids, molecules that are similar to those found in marijuana. But these cannabinoids occur naturally in the brain, and the study hinged on targeting specific cannabinoids.

"When you smoke a joint, you activate cannabinoid receptors all over the brain," explained Kreitzer, who now is a postdoctoral fellow at Stanford University and will soon move to a research position at the University of California, San Francisco. "That is indiscriminate," Kreitzer said. "In general, you need more specific signaling. Our approach involved only regions of the brain or cells that release dopamine."

Dopamine is crucial, because a lack of that chemical produces the movement problems seen in Parkinson's disease. Kreitzer and Dr. Robert Malenka, professor in psychiatry and behavioral sciences at Stanford, focused on dopamine in the striatum, a region of the brain implicated in Parkinson's disease and a number of other disorders.

"This particular part of the brain doesn't have any obvious anatomy," Kreitzer said. "If you just look at the cells, they all look alike. But it turns out that there are two specific circuits there involved in the control of movement -- a direct pathway that activates motion and an indirect pathway that inhibits motion."

The researchers worked with mice engineered to have a fluorescent protein in one of those circuits. They found that dopamine acts differently in the two circuits. When dopamine is depleted in the pathway that inhibits movement, it becomes overly active.

"The mice that didn't have dopamine in that circuit are completely frozen," Kreitzer said. "They don't walk around at all. To restore plasticity, we tried to activate the dopamine signal."

The mice were given both dopamine and a drug being developed for treatment of anxiety, which acts by slowing the breakdown of brain cannabinoids. "The animals started walking around immediately," Kreitzer said. "There was a five- or sixfold increase in motor activity. If you inhibit the breakdown of these endocannabinoids, you enhance activity even in mice that lack dopamine."

Research now will go in a number of directions, Kreitzer said. "We'd like to understand some other functions of these compounds," he said. Several stages of animal work must be done before human trials can be considered, Kreitzer added.

"A potential role for endocannabinoids for Parkinson disease represents an exciting new area for Parkinson research," said Dr. Michael S. Okun, medical director of the National Parkinson Foundation, which helped fund the research.

Although more study is needed, the work "sheds some light on potentially relevant targets and strategies for treatment of this neurodegenerative disease," said Okun, who is also co-director of the Movement Disorders Center at the University of Florida, Gainesville.

<span class=postbold>More information </span>

There's more on Parkinson's disease at the National Parkinson Foundation.

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Enhancing activity of marijuana-like chemicals in brain helps treat Parkinson's

February 7, 2007 09:47 PM
Biology News Net


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." Source : Stanford University Medical Center

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Story from BBC NEWS

Published: 2007/02/08 00:12:40 GMT

Brain 'cannabis' Parkinson's hope

<table class=posttable align=right width=205><tr><td class=postcell><img class=postimg src=bin/brain_bbc.jpg></td></tr></table><span class=postbold>Boosting levels of the brain's natural cannabis-like chemicals could improve the treatment of Parkinson's disease, a US study suggests. </span>

Mice with a similar condition could move normally within 15 minutes of having a cocktail including a compound which increases endocannabinoid levels.

But the scientists, writing in Nature, warned smoking cannabis would not have the same effect.

UK experts said the study increased understanding of Parkinson's.

<table class=posttable align=left width=300><tr><td class=postcap>
It is a long, long way to go before this will be tested in humans

Dr Robert Malenka, Stanford University

</td></tr></table>

Around one in 500 people in the UK have the disease.

It is a progressive, degenerative, neurological condition for which there is currently no cure.

Sufferers find increasing difficulty in moving their arms and legs. They develop tremors and facial tics, and gradually become more and more immobile.

<span class=postbold>Treatment combination</span>

The researchers, from Stanford University Medical Center in California, focused on an area of the brain called the striatum which has already been linked to Parkinson's.

The activity of nerve cells in the striatum relies on the chemical dopamine.

If there is too little dopamine in that area, Parkinson's disease can develop.

They used mice genetically modified to have a condition like Parkinson's and marked certain cells with a fluorescent protein that glowed vivid green under a microscope.

Their study indicated that two types of cells formed a "push-pull system" in the brain - one is thought to be involved in activating motion, while the other is likely to stop unwanted movement.

If there is too little dopamine, it is thought that the cells which restrict motion become dominant, making it harder for a person to move.

An existing drug which boosts dopamine levels led to a small improvement in the animals' condition.

But it was only when they added an experimental drug designed to slow the breakdown of endocannabinoids, being developed by Californian firm Kadmus Pharmaceuticals, that the mice showed a dramatic improvement.

The mice went from being unable to move, to moving freely in 15 minutes.

<span class=postbold>'Greater insight'</span>

Dr Robert Malenka, who led the study, said: "They were basically normal.

"This points to a potentially new kind of therapy for Parkinson's disease."

But he added: "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."

And he stressed that the study found the use of specific chemicals made the difference.

"That is a really important difference, and it is why we think our manipulation of the chemicals is really different from smoking marijuana."

Kieran Breen, director of research and development at the UK's Parkinson's Disease Society, said: "The study provides us with a greater insight into how the nerve cells in the area of the brain affected in Parkinson's are connected and how they communicate with one another.

"A greater understanding of this will provide information about the changes that occur when nerve cells die and may ultimately lead to the identification of new targets in the cell at which drugs can act to treat the symptoms of the condition."

<center><small>© BBC MMVII</small></center>

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Posted on Fri, Feb. 09, 2007

Brain chemical linked to Parkinson's symptoms

By CARL T. HALL
The Monterey County Herald

Neuroscientists have found that a substance similar to the active ingredient in marijuana but produced naturally in the brain helps to control mobility -- and may offer a novel target for treating Parkinson's disease.

The findings by Stanford University researchers, reported in the latest issue of the journal Nature, show how marijuana-like ''endocannabinoids'' -- one of the many chemicals used in the brain to transmit signals -- form part of the neural machinery that directs normal physical movement.

A shortage of the endocannabinoids, the scientists found, can knock the system out of balance to produce the characteristic tremor, rigidity and other mobility problems of Parkinson's disease patients.

The shortage arises when another signaling system in the brain, driven by the neurotransmitter dopamine, starts to break down. Without enough dopamine, the researchers found, brain cells stop producing endocannabinoids in the proper amount needed to control movement.

Researchers used mice specially bred so that target cells in the striatum -- a region deep in the brain where endocannabinoids and dopamine operate -- could be identified and recorded when the mice were given toxins to mimic the symptoms of Parkinson's. The mice were administered a drug combination -- potentially a precursor of a human experimental therapy -- to test the main findings.

One drug, called quinpirole, boosted dopamine -- a standard medical strategy in human cases. The other drug -- known as KDS-4103, being developed as a possible pain medication by an Irvine biotech company called Kadmus Pharmaceuticals Inc. -- blocked the action of an enzyme that degrades endocannabinoids in the brain.

The result of this one-two punch was a dramatic improvement in Parkinson's symptoms in the mice, according to the study authors, Dr. Robert Malenka and Anatol C. Kreitzer.

''The hope is that if the same sorts of things are going on in human brains, that maybe by using these drugs that boost levels of endocannabinoids, you will reduce the amount of dopamine drugs people have to be taking, or extend the usefulness of dopamine drugs, with less side effects,'' said Malenka during an interview. He was senior author of the Nature study.

If the combination proves to have a more potent effect than standard therapy in patients, ''it might allow people to move better, walk better, play tennis better,'' Malenka added.

That would take clinical studies to prove, with the possibility of years of preclinical research to even reach the human testing stage. Independent experts said it was an intriguing new lead for a condition that afflicts 1.5 million people in the United States.

''This is an extremely intriguing finding,'' said Joan Samuelson, president of the Parkinson's Action Network, a patient advocacy group. ''Science has been frustratingly slow in cracking the mystery of the peculiar pathology of Parkinson's.''

One thing the findings in Nature don't suggest is that smoking marijuana might help alleviate Parkinson's.

Any useful therapy would have to avoid overwhelming the delicate balance of the brain's movement-control apparatus, Malenka said, boosting neurotransmitters only where they are needed.

Smoking marijuana, by contrast, floods cannabinoid receptors scattered throughout the brain with THC, the active ingredient in the plant that mimics the brain's own signaling compound. That has potent effects but there's no evidence it can help problems in the dopamine-endocannabinoid system affected by Parkinson's disease.

''When you smoke a joint, or have THC on the brain, you're activating these receptors indiscriminately, all over the place,'' Malenka said. ''What you want is a more sophisticated and subtle perturbation of this endocannabinoid signaling system than you can get by smoking a joint.''