Monday, August 22, 2005

Scientists May Have Found Key To Spinal Cord Damage

Spinal Cord Injury

Purdue University researchers may have isolated the substance most responsible for the tissue damage that follows initial spinal cord injury, a discovery that could also improve treatments for a host of other neurodegenerative conditions.

A research team led by Riyi Shi (REE-yee SHEE) has found that a chemical called acrolein, a known carcinogen, is present at high levels in spinal tissue for several days after a traumatic injury. Although acrolein is produced by the body and is non-toxic at normally occurring low levels, it becomes hazardous when its concentration increases, as it often does in tissue that experiences stresses such as exposure to smoke or pesticides. That list of stresses now includes physical damage, and in the case of spinal injury, acrolein's hazard may be the key in causing debilitating paralysis that sets in after the initial trauma.

"When a spinal cord ruptures, not only are the traumatized cells at increased risk of damage from free radicals that oxidize the tissue, but the cells also spill chemicals that actually help the free radicals to launch repeated attacks," said Shi, who is an associate professor of neuroscience and biomedical engineering in Purdue?s School of Veterinary Medicine and Weldon School of Biomedical Engineering. "Our latest research indicates that acrolein may be the primary culprit that enables this vicious cycle. Because acrolein has already been implicated in cancer and neurological diseases, drugs that detoxify it could become important for treating not only spinal cord damage but a host of other conditions as well."

The research, which Shi carried out with his student Jian Luo and Koji Uchida of Japan?s Nagoya University, appears in the (still forthcoming) March 2005 issue of the scientific journal Neurochemical Research.

Free radical molecules are well-known enemies of bodily health, and for years, physicians have recommended a diet rich in antioxidants, such as vitamins C and E, which are able to attach themselves to free radicals, detoxifying them. While there is nothing inherently wrong with this approach, Shi said, it might not be getting at the root of some health problems.

"Antioxidants are good scavengers of free radicals, and it's certainly wise to have plenty of them circulating in your bloodstream," he said. "The trouble is that when free radicals start attacking tissue, it happens in a tiny fraction of a second, after which they are gone. But the acrolein that these attacks release survives in our bodies much longer, for several days at least, and its toxicity is well documented."

For example, acrolein has long been known to cause cancer when its concentration in the body rises, and not much is needed to be dangerous. When a person inhales smog or tobacco smoke, for example, the fluids lining the respiratory tract show an acrolein concentration of about a millimole, not much by measuring-cup standards, but still over 1,000 times more than usual.

"If you took a single grain of salt from a shaker and dissolved it in a liter jug, the water wouldn?t taste very salty," Shi said. "But even that would be more than a millimole, and that's much more acrolein than the body can handle at once."

Because a high concentration of acrolein also has been linked to neurodegenerative conditions such as Parkinson's, Huntington's and Alzheimer's diseases, all of which progress slowly and resist treatment, Shi's team decided to see if the chemical was present in another slow-developing, seemingly untreatable condition: the degeneration of the spinal cord after initial traumatic injury.

"Unlike most other parts of the body, spinal cord tissue does not heal after injury," Shi said. "After the initial shock, it actually gets worse. Science has long been aware that some chemicals the damaged cells release are part of the problem, but no one has ever been sure which chemicals are responsible."

When a spine is damaged, the change in its ability to function follows a well-defined pattern. In response to the initial shock, the spine immediately becomes completely nonfunctional but then starts to recover quickly. Over the course of the next few days, in response to the secondary damage, the spine?s function again begins to drop, and within about three days it has leveled off at a point of near non-functionality.

"What our group did was measure the levels of acrolein in the injured spines of 25 guinea pigs for several days following an injury," Shi said. "We found that levels of acrolein peak 24 hours afterward, and they remain high for at least a week. Because acrolein has such a long lifespan and is so toxic, we theorize that it is primarily responsible for the secondary damage that keeps injured spines from healing."

Acrolein's involvement with other conditions suggests that it could be the key to fighting a number of diseases, Shi said.

"When the brain suffers a stroke, for example, it is deprived of oxygen, which is often thought to be the cause of brain damage. But, in fact, you can starve the nervous tissue of oxygen for up to an hour without harm if only you control the acrolein levels," Shi said. "This paper suggests that the body is generally pretty resilient but that acrolein may be something it can't handle."

Shi said that some drugs already under development for other conditions could be used to treat neurodegenerative diseases as well.

"Hypertension drugs, which bind to acrolein and detoxify it, are already under study for their added potential to promote liver health," Shi said. "We would like to see whether they also could be modified to treat the conditions we are interested in."

Further research will be necessary to determine how great a role acrolein actually plays in the process of secondary spinal cord damage, but Shi said that once this role is clarified, drugs that counter acrolein's effects could join the other approaches to treating spinal cord injury under development at Purdue?s Center for Paralysis Research.

"My colleague Richard Borgens and I have already had our hands in developing PEG, a substance that coats damaged spinal cells so that their membranes can heal and also oscillating field stimulator implants that encourage the tissue to regenerate," Shi said. "We are hopeful that detoxifying acrolein will allow doctors to stop the chemical attack cycle as well, adding to the number of treatment methods available."

The center was established in 1987 both to develop and to test promising methods of treatment for spinal cord injuries. The center uses its close affiliation with the Department of Veterinary Clinical Sciences in the College of Veterinary Medicine to move basic laboratory methods into clinically meaningful veterinary testing.

This research was funded in part by the National Institutes of Health and the State of Indiana.

By Chad Boutin - WEST LAFAYETTE, Ind. - Purdue News
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Monday, August 15, 2005

Experimental Therapy Could Offer New Way to Treat Spine Damage

An experimental therapy that combines stem cells and gene therapy to repair spinal cord injuries in rats may lead to a new way to treat the same injury in humans.

The therapy, described in the July 27 issue of the Journal of Neuroscience, shows significant potential for repairing the spinal cord by regenerating a protective coating on the nervous system, said lead researcher Scott Whittemore of the University of Louisville.

"Other scientists have suggested this technique, but our study is the first to show that it really works," said Whittemore, the University of Louisville Henry D. Garretson Endowed Chair in Spinal Cord Injury Research and scientific director of the Kentucky Spinal Cord Injury Research Center.

Injuries to the spinal cord can damage myelin, a coating that protects the nervous system much like the insulation around an electrical cord. When myelin is damaged or destroyed, the nerves surrounding the spine cannot adequately conduct signals to and from the brain.

Whittemore found that stem cells grafted onto damaged spinal cords in rats can develop into cells that make myelin, which in turn grows and migrates to the damaged tissue. The new cells grow even faster when combined with a gene therapy that boosts production of two substances that help nerves survive and mature, he said.

"The key word here is 'combination,'" said Naomi Kleitman of the National Institute of Neurological Disorders and Stroke. "This is one of a series of new studies showing that a combination of therapies is needed for successful spinal repair."

Whittemore's study was funded by NINDS, National Institutes of Health, Kentucky Spinal Cord and Head Injury Research Trust, Norton Healthcare and several private foundations.

An initial $8.5 million Centers of Biomedical Research Excellence (COBRE) grant from the National Institutes of Health has been renewed, Whittemore announced Aug. 1. The grant will provide $10.4 million over five years.

This is the first COBRE grant at U of L to be renewed and signals the NIH's confidence in the research being undertaken at KSCIRC, said Larry Cook, executive vice president for health affairs.

Researchers at the center, one of the largest spinal cord injury research centers in the United States, are exploring ways to:

  • Prevent loss of nerve tissue after spinal injury promote regeneration of sensory and motor function after spinal cord injury rebuild the neural circuitry that controls locomotion modulate chemical pathways that control cell survival and cell death discover molecules that regulate spinal cord development.

  • Use gene therapy for spinal cord repair.


Since 1998, Whittemore and other faculty at the Kentucky spinal cord research center have received more than $32.5 million in research support aimed at developing new ways to repair spine injuries.
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Saturday, August 13, 2005

Long Beach International Marathon Partners w/ the Christopher Reeves Foundation and Paralysis Project

The Long Beach International Marathon Partners with the Christopher Reeves Foundation and Paralysis Project for Charity Marathon Program.

The Long Beach International Marathon on October 16, 2005, offering events including the 5k run/walk, 10K, Marathon, Marathon, Wheelchair Marathon, Inline Skate Marathon, and Bike Tour, has collaborated efforts with the Paralysis Project and Christopher Reeve Paralysis Foundation to offer online and offline fundraising services for participants interested in raising money for these organizations. The services will include personalized Web pages for each fundraiser that offer the ability to collect donor contributions online, as well as a professional fundraiser kit with tips on how to fundraise, plus forms and instructions on how to collect checks from family and friends.

"This program gives people who would like to support these organizations an easy and fun way to fundraise while providing them the opportunity to get active and participate in one of the marathon events." Allison Reutter, Fundraising Program Coordinator. "Many people who are dealing with Spinal Cord Injury can compete in the Wheelchair division of the Marathon and raise money to help these causes get closer to a cure."

Participants involved in the fundraising efforts will be entered into a raffle to win prizes ranging from a big screen TV to free round trip airfare. Each fundraiser will also receive a free entry into the fundraiser kick-off party, offered to all new fundraisers giving them a chance to meet others supporting the same cause, and receive professional training tips.

The Christopher Reeve Paralysis Foundation (CRPF) is dedicated to funding research that develops treatments and cures for paralysis caused by spinal cord injury and other central nervous system disorders. The Foundation also vigorously works to improve the quality of life for people living with disabilities. The mission of Paralysis Project is to accelerate progress toward finding a cure for paralysis caused by spinal cord injury (SCI). Each year, the lives of more than 14,000 are shattered by SCI resulting from sports injuries, motor vehicle accidents, falls, and acts of violence. Over the past 14 years, Paralysis Project has raised millions to fund progressive research on spinal cord repair and regeneration to help these people walk again.

Every 48 minutes, an American is spinal cord injured. Please help us in our effort to unite for a cure by fundraising for one of these incredible organizations. If you would like to join the fundraising team for the Paralysis Project you can sign up at www.active.com/donate/pplb.

If you would like to fundraise for the Christopher Reeves Foundation please call (858)964-3952.

Sign up for the Long Beach International Marathon at www.runlongbeach.com.
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Monday, August 01, 2005

Stem Cells Heal Spinal Injuries

GENETICALLY engineered stem cells can help rats' severed spinal cords grow back together, according to a study published today.

Rats given the treatment, using stem cells taken from rat embryos, could move their legs again after their spines were severed in the lab, said the researchers' report in the Journal of Neuroscience.

The scientists hope the approach, which generated a new fatty cover for the spinal cord cells called the myelin sheath, also could be shown to work in people.

The key is using the right stem cells and then stimulating them correctly, said the researchers, who were led by Scott Whittemore of the University of Louisville School of Medicine in Kentucky.

"These findings suggest the possibility that transplantation therapy using a subset of neural stem cells and neurotrophic factors might improve functional recovery in human spinal cord injury," said Dr Michael Selzer, a professor of neurology at the University of Pennsylvania Medical Centre in Philadelphia.

Spinal cord injuries can be caused by accidents or infections and affect 250,000 people a year in the United States alone, costing $US4 billion ($5.25 billion) annually, according to the National Institute of Neurological Disorders.

Whittemore's team took specific cells from rat embryos called glial restricted precursor cells - a kind of stem cell or master cell that gives rise to nerve cells.

They genetically engineered these cells to do a little extra work by producing a compound called a growth factor - in this case, a new one called multineurotrophin. It was designed to coax immature neural stem cells to mature and become specialised cells called oligodendrocytes.

Oligodendrocytes help myelin grow onto nerve fibres, which cannot grow or function without this fatty protective coating.

Two-thirds of the rats in the study regained some hind limb movement, the researchers said.
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Nerve-insulating substance, Myelin, may lead to functional improvements in animals with spinal cord injury

Combining partially differentiated stem cells with gene therapy can promote the growth of new "insulation" around nerve fibers in the damaged spinal cords of rats, a new study shows.

The treatment, which mimics the activity of two nerve growth factors, also improves the animals' motor function and electrical conduction from the brain to the leg muscles. The finding may eventually lead to new ways of treating spinal cord injury in humans. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS).

The new study provides the best demonstration to date that producing a nerve-insulating substance called myelin can lead to functional improvements in animals with spinal cord injury. Previous studies have shown that the loss of myelin around nerve fibers contributes to the impaired function after a spinal cord injury. However, until now it has not been clear whether promoting new myelin growth in the spinal cord can reverse this damage, says Scott R. Whittemore, Ph.D., of the University of Louisville in Kentucky, who led the new study. "Many other investigators have suggested that remyelination is a possible approach to repair the spinal cord, but this is the first study to show unequivocally that it works," says Dr. Whittemore. "It is a proof of principle." Although the finding is promising, much work remains before such a technique could be used in humans. The study appears in the July 27, 2005, issue of the Journal of Neuroscience.

In the study, the researchers took cells called special cells called glial-restricted precursors from the spinal cords of embryonic rats. These precursor cells develop from stem cells and are specialized so that they can form only two kinds of cells: astrocytes, which help support neurons and influence their activity, and oligodendrocytes, which produce myelin. The scientists used a modified virus to insert genes for marker proteins that make the cells visible. Some cells also received a gene called D15A. This gene produces a protein with activity similar to growth factors called neurotrophin 3 (NT3) and brain-derived neurotrophic factor (BDNF). Both NT3 and BDNF help myelin-producing cells (oligodendrocytes) develop and survive.

Dr. Whittemore and his colleagues injected the treated precursor cells into the spinal cords of rats with a type of spinal injury called a contusion, which is caused by an impact to the spinal cord. Other groups of spinal cord-injured rats received just precursor cells, D15A gene therapy, or other treatments that were used for comparison. The rats were evaluated weekly for 6 weeks after the treatment using a behavioral test called the Basso-Beattie-Bresnahan scale, which measures characteristics such as weight support, joint movements, and coordination. The researchers also used an electrical current test in which they put a magnetic stimulator on the skull and measured whether the resulting electrical current was transmitted to a muscle in one of the hind legs.

Most of the rats treated with the combination of precursor cells and gene therapy improved significantly on both tests, the researchers found. The combination therapy led to an improvement in the rats' ability to walk and about a 10 percent improvement on the electrical current test. Rats that received the other treatments did not improve significantly, and untreated rats did not have any electrical activity that passed through the damaged spinal cord. Studies of the damaged spinal cord tissue after the combined treatment showed that many of the transplanted cells survived and migrated within the cord and that about 30 percent of them developed into myelin-producing oligodendrocytes.

"The key word here is 'combination.' This is one of a series of new studies showing that a combination of therapies is needed for successful spinal repair, in this case, specialized cells and growth factors. The experiments also used a combination of outcomes -- physiology, behavior, and anatomy -- to point clearly at myelination as the cause for improved function," says Naomi Kleitman, Ph.D., the NINDS program director for the grants that funded this work. "The study also is a good example of strong collaboration between two spinal cord injury research centers, one at the University of Louisville and the other at the University of Miami in Florida."

The researchers are now investigating ways to improve this type of therapy with additional genetic modifications to the transplanted cells, and they plan to test similar techniques that start with undifferentiated embryonic stem (ES) cells instead of glial-restricted precursor cells. ES cells would be better for human studies than glial-restricted precursors because ES cells can be more readily obtained, Dr. Whittemore says.
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