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Marijuana-like substance in brain could help treat Parkinson's
02.07.07|SFGate.com|Carl T. Hall

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."