University News Service

Study gets major boost to probe toxin's role in spinal injury, potential treatment

WEST LAFAYETTE, Ind. - Researchers have received $1.5 million to study the role of a toxin thought to worsen the severity of spinal cord injuries and to learn whether reducing its concentration in the days following trauma also decreases damage that can lead to paralysis.

"Spinal cord injury is a devastating medical condition with no effective treatments despite decades of research efforts," said Riyi Shi (pronounced Ree Shee), lead researcher on the project and a professor in Purdue University's Department of Basic Medical Sciences, College of Veterinary Medicine, Center for Paralysis Research and Weldon School of Biomedical Engineering.

The new funding from the National Institutes of Health will enable researchers to study why spinal cord damage often grows worse in the days and weeks after the initial injury.

"Often what happens is that people are injured, but the initial injury may not seem that serious," Shi said. "However, over the coming hours and days the injury intensifies, the damage site expands and may become much worse, sometimes resulting in permanent paralysis."

A toxin called acrolein is produced within the body after nerve cells are damaged, triggering a cascade of biochemical events thought to worsen the injury's severity. The work also will probe whether two drugs might be used to control the toxin's concentration to possibly reduce the severity of the injuries.

"This research will no doubt significantly enhance our understanding of the pathology of spinal cord injuries," Shi said.

Researchers theorize that the initial injury produces harmful compounds called oxygen free radicals, which then damage lipids, proteins and DNA in spinal tissue. The damaged lipids generate acrolein, which stimulates certain enzymes that then produce more free radicals, starting the cycle over again.

"We think this results in a vicious cycle that forms the major basis of the second wave of injury," said Shi, who has been studying the potential role of acrolein in spinal cord injuries for a decade. "It is possible that we might not only be able to treat the secondary injury, but if we intervene early enough we might be able to actually prevent it."

Acrolein can remain active far longer than short-lived free radicals and also can directly damage proteins, DNA and lipids. 

"As a part of an organized effort to expose acrolein as a culprit in spinal injury, we will measure a metabolic product of the toxin in the urine of rats with spinal injuries," Shi said. "Using this technique, acrolein levels can be monitored non-invasively and then linked to disease severity and progression, ultimately providing valuable information for diagnosing and treating disease in many animal species and, eventually, humans."

The researchers will analyze urine in animals that have suffered a spinal cord injury, working with Bruce Cooper, director of the Metabolite Profiling Facility in the Bindley Bioscience Center of Purdue's Discovery Park. The facility will use highly sensitive techniques to measure the metabolic products of acrolein in the urine.

"We believe that using this technology to monitor acrolein will provide a great benefit in treating human spinal injury patients," Shi said. "By periodically measuring this molecule in the urine, it is possible to document how its levels change in animals over the weeks following the injury without euthanizing them."

The researchers will study the use of two drugs, hydralazine and phenelzine, which have been approved by the U.S. Food and Drug Administration for hypertension and depression, respectively. Preliminary data have shown that hydralazine reduces the concentration of acrolein in animals with spinal cord injuries and improves motor behavioral recovery.

"If you inject these drugs into the animal systemically, they can get into the spinal cord within two hours," Shi said. "In addition, the dosage of hydralazine to trap acrolein appears to be significantly lower than that already used to combat hypertension. If the work with animals is successful, it will likely be extended through human clinical trials and, if proven effective, become a treatment option for patients."

Others involved in the research are Daniel Smith, a research scientist at Purdue's School of Pharmacy, and Xiao-Ming Xu, scientific director of the Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute at the Indiana University School of Medicine, both of whom are long-time collaborators of Shi.

Findings could be useful in the study of acrolein's possible role in other diseases, including multiple sclerosis, Alzheimer's disease, cancer and atherosclerosis. Previous work was supported with funding from the state of Indiana.

Writer: Emil Venere, 765-494-4709, venere@purdue.edu

Source: Riyi Shi, 765-496-3018, riyi@purdue.edu