Parkinson's disease: Treatment breakthrough in mice opens new path

http://dailynews.muzi.com/news/ll/en...10035633.shtml
2007-02-07

Lab mice with Parkinson's disease were able to move normally after researchers treated them with a classic anti-Parkinson's drug and a compound to slow the breakdown of naturally-occurring marijuana-style chemicals in the brain.

Mice which had been genetically engineered to have the symptoms of Parkinson's, a degenerative disease that causes trembling, jerkiness and rigidity, went from being frozen in place to moving around freely in 15 minutes after the combination treatment.

The research, led by Robert Malenka and Anatol Kreitzer of Stanford University Medical Center in California, is published on Thursday in Nature, the weekly British science journal.

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

"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 (brain) circuits that are malfunctioning in this disease."

Parkinson's is linked to a depletion of a brain chemical called dopamine in a part of the brain called the substantia nigra.

As a result, less dopamine goes to the striatum, the part of the brain that helps coordinate motion.

To compensate for this shortage, patients with Parkinson's are given drugs that stimulate or mimic dopamine, although these treatments often have bad side-effects and can start to wear off after a few years.

Working on mice, Malenka's team discovered that the striatum has two distinct types of cell, each forming a circuitry that initiates motion or restrains unwanted movement.

One of the cell types turned out to have a sort of dopamine receptor -- a docking point on the cell's surface -- that the other cell did not have.

The team turned to previous work into dopamine and endocannabinoids, as the naturally-occurring marijuana-like compound is called.

Their hunch was that the two chemicals worked together to ensure smooth activation of the cell and its circuitry, which they believe inhibits unwanted movement.

They combined a dopamine mimic called quinpirole, with a new test compound, URB597, that slows the way enzymes break down endocannabinoids in the brain.

"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," said Kreitzer.

"But when we gave the two together, the animals really improved dramatically."

Kreitzer and Malenka caution Parkinson's patients against the idea of smoking marijuana to try to achieve the same result.

They point out that their technique aims at stimulating the activity of endocannabinoids in a selected part of the brain where it occurs naturally.

This process is the opposite, and more finetuned, compared to boosting levels of endocannabinoids across the brain by smoking the drug.

According to research published in the latest issue of the journal Neurology, the number of people with Parkinson's in 15 of the world's largest nations will double, from 4.7 to 8.7 million, by 2030.

Most of the rise will be in developing countries, especially China.

Parkinson's disease is linked to old age. Thus an ageing population, coupled to greater longevity and past demographic growth, will bring a rise in the number of cases.

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Natural brain substance linked to Parkinson's symptoms

Carl T. Hall, Chronicle Science Writer
Thursday, February 8, 2007
http://www.sfgate.com/cgi-bin/articl...&feed=rss.news

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."