A Way to Slow Parkinson's?

Blocking Specific Form of a Brain Chemical Could Slow Brain Cell Loss, Researchers Find

By Daniel DeNoon
WebMD Medical News
http://www.webmd.com/content/article...src=RSS_PUBLIC

Sept. 12, 2006 -- Blocking a specific form of a brain chemical slows brain cell loss in an animal model of Parkinson's disease, Texas researchers report.

In the animal model, the researchers found they could slow the death of affected brain cells by about half by blocking the chemical, called soluble TNF.

The finding offers a target for new drugs that could slow the progression of the debilitating and deadly disease. And it may apply to Alzheimer's disease as well, suggest University of Texas Southwestern Medical Center researchers Melissa K. McCoy, Malú G. Tansey, PhD, and colleagues.

The finding "may unveil opportunities for development of new … therapeutics to treat human neurodegenerative diseases like Parkinson's disease and Alzheimer's disease," McCoy and colleagues say.

The researchers report their study in the Sept. 13 issue of The Journal of Neuroscience.

Parkinson's Culprit Found?

Parkinson's happens when about 80% of a specific kind of brain cell mysteriously dies off. McCoy and colleagues note that this seems to involve one of the body's most basic immune responses -- inflammation.

Messenger chemicals trigger this process. One of those chemical messengers is tumor necrosis factor, or TNF.

You may have read about TNF before. It's involved in the haywire immune responses that cause rheumatoid arthritisrheumatoid arthritis.

The UTSW researchers decided to look at a specific form of TNF called soluble TNF. That's because the kind of brain cells that die off during Parkinson's disease are highly sensitive to that brain chemical.

Sure enough, in an animal model of Parkinson's disease, they found that by blocking soluble TNF, the rate of brain cell death could be about cut in half.

That, they suggest, would be enough to significantly slow the inexorable, deadly progression of Parkinson's disease.

Current arthritisarthritis drugs Enbrel and Remicade block TNF. But they block a form of the chemical important to immune function and infection resistance.

For Parkinson's disease, McCoy and colleagues suggest a drug that specifically blocks soluble TNF would be safer.

There's also evidence from mice studies that TNF signaling may be important in Alzheimer's disease, too. McCoy and colleagues say a drug that blocks soluble TNF might kill two birds with one stone.

Blocking soluble TNF does not stop the death of important brain cells -- it only slows the process. But the researchers say this could be enough to make a major impact.

"A reduction of [brain-cell] death by 50% with delivery of [TNF-blockers] into the central nervous system would have a significant and positive impact on delaying progression of [brain cell] loss in individuals with Parkinson's disease, should these results in animal models be realized in clinical trials," they say.

SOURCES: McCoy, M. The Journal of Neuroscience, Sept. 13, 2006; vol 26.

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TNF: Tumor necrosis factor. A type of biological response modifier (a substance that can improve the body's natural response to disease). Tumor necrosis factor- (TNF-), a cytokine secreted by adipose tissue and other cells

Cytokine: Any of several regulatory proteins, such as the interleukins and lymphokines, that are released by cells of the immune system and act as intercellular mediators in the generation of an immune response.

Adipose Tissue: A type of connective tissue specialized for lipid (fat) storage.

Pre-clinical study finds Parkinson's cell death blocked by stopping inflammatory factor

EurekaAlert!
Public release date: 12-Sep-2006

http://www.eurekalert.org/pub_releas...-psf090706.php

DALLAS – Sept. 12, 2006 – Blocking one of the body's natural inflammatory factors gives substantial protection against cell death in the brain associated with Parkinson's disease, researchers at UT Southwestern Medical Center have found in a study on rats.

By using a drug against an inflammatory molecule called tumor necrosis factor or TNF, the researchers saw a 50 percent drop in dopamine neuron death in the brains of rats injected with compounds that cause Parkinson's-like cell death.

"Our findings suggest that TNF-dependent inflammation may be part of the progressive features of Parkinson's disease, and this gives us an opportunity with anti-TNF therapy to slow down or prevent the progression of the disease," said Dr. Malú Tansey, assistant professor of physiology at UT Southwestern and senior author of the study. "Our prediction is that independent of the environmental toxin or trigger that induces its production in the midbrain, TNF is likely to be a common mediator of dopamine neuron death."

The research will appear online and in the Sept. 13 issue of the Journal of Neuroscience.

Tumor necrosis factor is necessary for a functioning immune system. Its effects include the local inflammation and redness around wounds, and the painful swelling around joints in rheumatoid arthritis. TNF also activates other cells – including cells in the brain called microglia – that eat bacteria and other pathogens.

While the results point in a direction for treating neurodegenerative diseases with anti-inflammatories, a few problems will need to be addressed before anti-TNF therapies could come into widespread use to fight neurodegeneration, Dr. Tansey said. For instance, commercially available anti-TNF drugs as well as the new drug used in this study are too large to independently cross from the bloodstream into brain tissue.

Parkinson's disease affects 5 percent of people over 65, and is the second most common neurodegenerative disease after Alzheimer's. Parkinson's disease comes about because of the death of a certain class of nerve cells in an area of the brain called the substantia nigra. By the time serious symptoms appear, more than 80 percent of the dopamine-producing nerve cells are already dead, and the damage is irreversible.

In addition to its beneficial role, TNF has been a suspected player in Parkinson's because elevated levels of it are found in post-mortem brains and cerebrospinal fluid of people with the disease. A previous study by other researchers found that non-steroidal anti-inflammatory drugs that block production of TNF and related molecules can reduce the risk of developing Parkinson's by 46 percent.

In the current study, UT Southwestern researchers injected two different substances into the rats' brains to cause cell death in the substantia nigra – low-dose infusion of LPS, a toxin from bacteria often used to mimic chronic inflammation of the central nervous system, and 6-hydroxydopamine, which kills cells by creating an overwhelming amount of reactive oxygen and nitrogen molecules. Cell death was measured by counting neurons in stained brain slices.

When an experimental TNF inhibitor called XENP345, designed specifically to block soluble TNF, was also introduced into the brain, dopamine neuron death was reduced by about half.

The same effect was found on cultured dopamine neurons exposed to either toxin.

The researchers are now looking into why TNF inhibition did not fully protect against cell death. For example, the drug may not have been able to fully diffuse throughout the tissue, it might take longer to work than the weeks allowed in the experiment, or dopamine neuron loss might also involve processes independent of TNF.

"If an intervention could still reduce the extent or rate of cell death by 50 percent, it could make a huge difference in the life of a Parkinson's disease patient," Dr. Tansey said.