Jan. 31, 2000 WEST LAFAYETTE, Ind. – A brief application of a polymer commonly used in medicine and cosmetics has been shown to immediately repair damaged nerve membranes in live guinea pigs with severe spinal cord injuries.
The polymer, called polyethylene glycol or PEG, works by "fusing" the membranes of damaged nerve cells, and it can be applied up to eight hours after the injury without adversely affecting the patient's recovery.
The process may someday be used in humans with spinal cord injuries to minimize or reverse the damage to nerve cells that results in paralysis, says Richard B. Borgens, professor of developmental anatomy at Purdue University.
"It's the disruption of the membrane that leads to the death of the cell," Borgens says. "In this case, we're talking about a mechanical injury to nerve cells, which conduct the impulses needed for movement and a variety of other functions. If the nerve cell dies or separates, paralysis will occur."
Borgens says this is the first study to demonstrate such a rapid recovery of function and nerve conduction in the whole animal with a spinal cord injury.
He and his colleague, Dr. Riyi Shi, both of Purdue's Center for Paralysis Research in the School of Veterinary Medicine, report their findings in the January issue of the FASEB Journal, a publication of the Federation of American Societies for Experimental Biology. A year ago, they reported similar results in tests conducted on spinal cords that had been removed from guinea pigs.
The findings offer the promise of rescuing substantial portions of damaged spinal cord at the time of initial surgery, Borgens says. The researchers plan to move the technique into clinical testing later this year, using paraplegic dogs with naturally occurring injuries.
Because the treatment can be given up to eight hours after the injury without losing benefits, PEG may someday be used in addition to the drug methylprednisolone as an emergency treatment for spinal cord injuries, says Borgens.
PEG is a nontoxic, water-soluble polymer widely used in medicine and cosmetics. In the study, Borgens and his team applied the substance across a region of the guinea pig's crushed spinal cord.
"In most spinal cord injuries in animals and in people, the spinal cord is not completely severed, but is more likely to be crushed," he says. "It is this crushing or compression of the spinal cord that causes the nerve fibers to develop holes in their membranes, which ultimately leads to cell death and separation of the nerve fiber within 24 to 72 hours. If the nerve fibers separate, or otherwise do not conduct impulses, paralysis will occur."
PEG was applied for two minutes, then removed. One group of animals received the application immediately after the injury, while a second group of animals was treated with PEG eight hours after the injury. Following the PEG applications, all the animals were tested to measure their ability to conduct nerve impulses through the spinal cord and to gauge their recovery of functional behavior.
Nerve impulses through the spinal cord were measured by stimulating a nerve in the hind leg and determining whether and when the impulses arrived at the brain.
Of the 47 guinea pigs used in the study, all 25 of the animals that received PEG were able to recover some nerve conduction – from 20 percent to 50 percent – within 15 minutes after PEG was applied. Measurements taken days and weeks later showed that, in addition, the nerve conduction recovery continued to improve up to one month after the initial treatment.
Of the 22 animals that did not receive PEG, not one animal recovered the ability to conduct nerve impulses through the spinal cord, Borgens says.
"Amazingly, one hundred percent of the PEG-treated animals recovered their ability to conduct nerve impulses, while none of the control animals did," Borgens says. "By measuring the quantity of nerve impulses that travel through the spinal cord, we can better index the integrity of the spinal cord after an injury."
To analyze the animals' functional or behavioral recovery, Borgens and his group used a measure called "skin rippling," a behavior found in many animals but not in humans. Formally called the CTM reflex – for cutaneous trunci muscle reflex – the behavior can be observed as a corrugated rippling of back skin in response to light tactile stimulation, for example, when a cat's back is tickled or when a horse is assailed by flies.
Borgens says the CTM reflex is an ideal tool for studying recovery of spinal injuries because the anatomy of the reflex is well understood and documented – from the sensation of tickling on the skin to nerve impulses traveling up the spinal cord, to the motor nerves and back out to the skin.
"We know all the connections, the complete circuit, and that's very powerful when tracking the flow of nerve impulses to see where they still exist or where they are blocked," he says. "Also, this is a behavior that is often permanently lost after severe spinal injury."
To visualize and measure the CTM behavior prior to injury, the shaved back of each sedated guinea pig was touched lightly with a probe, producing contractions of the skin. The scientists used markers to indicate areas on the animals' backs that rippled in response to the stimulus. In addition, the process was videotaped to record the animals' behavior.
The animals were videotaped again after the injury to show what part of the behavior was lost. After PEG was applied, the researchers used a pair of electrodes to stimulate nerve impulses through the spinal cord. In animals that showed behavioral recovery, the researchers compared the new movements with the videotapes made prior to the injury to measure the amount of recovery.
"Only three of the sham-treated animals recovered some behavioral function after the injury, but overall they tended to get worse with time," Borgens says. "Twenty of the 25 animals treated with PEG recovered variable amounts of CTM functioning, which continued to improve with time."
Borgens says the skin rippling test is a more reliable measure of post-injury behavior than tests designed to measure walking, because, unlike people, rats and some other animals can continue to walk after severe spinal cord injuries.
"In rats and guinea pigs much of the process of walking is controlled at a specific location on the spinal cord, and is less dependent on nerve impulses traveling to and from the brain," he says.
Though none of the animals showed a complete recovery of nerve conduction function, Borgens says that regaining 20 percent to 50 percent of the function is significant.
"If you have even 5 percent of the nerve fibers carrying nerve impulses, you'll get significantly more than 5 percent back in terms of restored behavior," he says.
Borgens says the technique may be a revolutionary new way of dealing with injuries to the nervous system: "It's too soon to know whether it would help patients with old injuries, but it is likely to be useful in treating recent injuries."
Borgens and Shi plan to conduct clinical trials in natural cases of paraplegia in dogs sometime this year. Human clinical trials are at least two years away.
The research was sponsored by the state of Indiana, through support of the Purdue-Indiana University Institute for Applied Neurology, and through gifts from Helen Skinner and Mary Hulman George.
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