Researchers at Purdue University may have isolated the substance most responsible for the tissue damage that follows initial spinal cord injury, a discovery that could revolututionise 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. 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.
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