Increasing levels of uric acid, a metabolic breakdown product found in blood and urine, may help cut some of the potentially devastating "secondary" cellular damage that occurs following a spinal cord injury, say researchers at Jefferson Medical College. The finding may lead to new treatments for such injuries.
After a spinal cord injury, the body's inflammatory response may actually make things worse, releasing a variety of potentially harmful chemicals that can make the injury more severe. J. Craig Hooper, Ph.D., associate professor of microbiology and immunology at Jefferson Medical College of Thomas Jefferson University in Philadelphia and at Jefferson's Kimmel Cancer Center and his colleagues there and at the University of Messina in Italy looked at whether uric acid treatment could actually prevent some of this secondary damage following such an injury in mice. Uric acid was known to reduce inflammation damage related to a compound call peroxynitrite.
They found that mice that received uric acid just before and right after an experimental spinal cord injury recovered motor function both faster and to a greater extent than mice that received only saline. Subsequent tests found that the uric acid actually prevented inflammation and some damage. Tests in cell culture showed that uric acid protected spinal cord neurons from peroxynitrite-related damage. The scientists report their findings Feb. 14, 2005 in the Proceedings of the National Academy of Sciences.
According to Dr. Hooper, secondary spinal cord damage – the so-called destructive cascade – begins within a few hours after the initial injury. "The effect is driven by nonspecific cells such as neutrophils," he explains, a type of white blood cell and a key player in the body's inflammatory response to injury. "We know neutrophils make peroxynitrite, which is a major trigger in opening the blood-brain barrier."
Dr. Hooper says peroxynitrite is known to contribute to cell damage in neurodegenerative disorders, and is known to be produced as a result of the body's inflammatory response.
"In the paper, we showed that uric acid modulates peroxynitrite's effects," Dr. Hooper says. "It's incredibly useful in preventing the damage related to peroxynitrite as a toxic molecule. More importantly, it stops the secondary injury cascade by preventing the neutrophils from getting into spinal cord tissues through the blood-brain barrier."
Dr. Hooper and his co-workers compared injured rats that received saline to spinal cord-injured rats that were given uric acid. "The injury causes a tremendous amount of damage in the mice – less than 50 percent range of motion in one or two hind limb joints remain immediately following the injury," he says. Those given saline had regained movement of up to two or three joints. The uric acid-treated rats recovered to where they could support their own weight, despite having some disabilities due to the damage.
Next, the scientists want to better understand how the peroxynitrite-mediated processes actually work, which is particularly important to learning how to control immune responses in the central nervous systems of both in mice and humans. "We're looking at various models to distinguish between peroxynitrite pathology and its effects on blood-brain barrier function," he says.
"We want to establish the precise timing where the inactivation of peroxynitrite will have therapeutic benefit," he says. "In the spinal cord, we know many of the changes occur within 24 hours. It's certainly feasible to give someone uric acid immediately and raise levels in 50 minutes. Whether or not this should be a first-line response is unknown.
"There is a range we could work with in raising levels before there's a problem, such as in gout," he says, referring to an ailment characterized by excessive uric acid. "We know that the human uric acid baseline is higher than that in mice, but we also know that the damage we see in the human spinal cord after injury is very similar to that seen in the mice.
"Raising uric acid levels in humans similarly to the rise we cause in the mouse should be sufficient to block peroxynitrite," Dr. Hooper says. "Our natural levels of uric acid are not sufficient. Moreover, someone with lower levels who has a spinal cord injury could definitely suffer greater damage."
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