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Default Boosting endocannabinoids + dopamine drug helps mice

Marijuana-like substance in brain could help treat Parkinson's, researchers say

Carl T. Hall, Chronicle Science Writer

(02-07) 10:59 PST SAN FRANCISCO -- 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.

Stanford University researchers reported today in the journal Nature that marijuana-like "endocannabinoids" -- one of the many chemicals used in the brain to transmit signals from one neuron to another -- form part of the neural machinery that directs normal movement.

THC, the active ingredient in marijuana, activities the same class of receptors as the natural chemicals but has effects throughout the brain, and no demonstrated benefits in terms of improved mobility.

In the latest study, experiments in mice found that a shortage of the natural marijuana-like compounds in a deep part of the brain known as the striatum seemed to help explain the tremors, rigidity and other symptoms of Parkinson's, one of the most common neurological disorders. Researchers hope to use the insight to find new ways to alleviate symptoms and perhaps improve current treatments.

The shortages arise when another signaling system in the brain, driven by the neurotransmitter dopamine, starts to break down. Without enough dopamine, the scientists found, the striatum stops producing endocannabinoids in the proper amount, creating an imbalance in the brain's delicate motor-control system.

Researchers used mice specially bred to have brains cells that could be identified and recorded when they were given toxins to mimic the symptoms of Parkinson's. A drug combination -- potentially a precursor of a new human therapy -- was administered to test the 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.

In effect, this allowed the brains of the rodents to make better use of the natural signaling molecules of movement. The result of this one-two punch was a dramatic improvement in symptoms, 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," Malenka, who was senior author of the Nature study, said during an interview.

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, and possibly 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.

Endocannabinoids were long suspected to play a critical role in the neurobiology of movement. The new study "specifies one of the exact mechanisms by which endocannabinoids can influence motion and mobility in Parkinson's," said Dr. George Kunos, who has studied the brain chemicals as scientific director of the National Institute on Alcoholism and Alcohol Abuse, a part of the National Institutes of Health.

Authors of the Nature study "raise the possibility of a combination therapy that would allow the dopamine part of the combination to be reduced," Kunos said, which "could reduce the unwanted side effects, and that could make a difference."

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

Malenka described the brain's natural system as an exquisitely sensitive combination of neurons and signaling molecules that inhibits movement, and a parallel circuit that activates movement. Tiny amounts of the endocannabinoids work in the inhibitory circuit.

Any useful therapy would have to be given in ways that enhance the desired inhibition, without overwhelming the balance of the brain's control apparatus, he said.

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. That's like hitting your brain with a sledgehammer."


Enhancing Activity of Marijuana-Like Chemicals in Brain Helps Treat Parkinson’s Symptoms
Marijuana-like chemicals in the brain may point to a treatment for the debilitating condition of Parkinson’s disease.

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.

Stanford University Medical Center integrates research, medical education and patient care at its three institutions — Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children’s Hospital at Stanford. For more information, please visit the Web site of the medical center’s Office of Communication & Public Affairs at
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