Spinal Injury
Proteoglycans in the net limit functional regeneration and plasticity after spinal cord injury. The chondroitinase enzyme removes the net and allows for regeneration and functional recovery, especially at chronic stages. [Case Western Reserve University School of Medicine]
An estimated 250,000 to 500,000 spinal cord injuries (SCIs) occur worldwide each year. Severe cases result in partial or complete paralysis, and in more than 50% of SCIs, the patient will also have breathing problems because the diaphragm is affected. Studies by researchers in the U.S. and U.K. have now demonstrated that long-term diaphragm function and partial limb function can be restored in rats with chronic SCI following just a single injection of an enzyme, chondroitinase ABC (ChABC). They hope that the treatment may also work to restore motor function in human patients with SCI.

“For the first time we have permanently restored both breathing and some arm function in a form of high cervical, chronic spinal cord injury-induced paralysis,” stated Jerry Silver, Ph.D., professor of neurosciences at Case Western Reserve University School of Medicine, and senior author of the scientists’ report in Nature Communications. “The complete recovery, especially of breathing, occurs rapidly after a near lifetime of paralysis in a rodent model.” The researchers describe their findings in a paper entitled, “Rapid and robust restoration of breathing long after spinal cord injury.”

The ability to re-establish and maintain essential motor function after long, paralyzing SCI is “a daunting prospect” that has so far proved elusive, the authors write. “This has led to the long-standing belief that robust functional recovery chronically is far more difficult, if not impossible, to achieve.”

Prior studies have suggested that some level of respiratory muscle activity can be restored by treatment with ChABC administered soon after cervical hemisection—when the spinal cord is half severed. The enzyme breaks down a type of proteoglycan that inhibits new axonal growth, “facilitating axonal regeneration or sprouting and enhancing synaptic strength.” However, these previous results indicated that administering ChABC immediately after SCI only results in about a 10% recovery of respiratory muscle activity.

In their new studies, rats with SCI half severed spinal cord at cervical vertebra C2 were given a single injection of ChABC below the SCI site, but treatment was administered three months after the injury, which in each case was a half severed spinal cord at cervical vertebra C2. “The strategy was to use a simple, one-time injection of an enzyme, chondroitinase, that breaks down the inhibitory proteoglycan molecules,” Dr. Silver explained. “The enzyme was administered, not within the lesion itself, but lower down within the spinal cord where motor nerve cells reside that send axons out to the diaphragm and forearm.”

In as little as a week after the ChABC injection new nerves started to grow and restore diaphragm function on the damaged side in 60% of animals. Within two weeks every treated animal demonstrated improvements, even though they had been paralyzed for most of their lives. “Surprisingly, the technique worked far better at chronic stages than at acute stages after injury,” said Dr. Silver.

Although injured animals were able to walk, feed, and drink normally, they had problems using the forelimb on the damaged side. Within a week of ChABC treatment, 70% of the animals were better able to use the affected forelimb, compared with just 30% of control animals. “Animals receiving the enzyme more readily used both limbs to move about and explore their environment,” the team noted.

Even greater benefits were seen when the animals received the ChABC injection in combination with a form of respiratory therapy known as intermittent hypoxia (IH), during which they are exposed to brief periods of low oxygen. Previous studies had indicated that acute repetitive IH therapy can result in small improvements in respiratory function following sub-chronic SCI. “When ChABC was combined with IH, diaphragm activity increased to ~40%,” the researchers continued. “Application of ChABC (with or without IH) resulted in the restoration of synchronized diaphragm function ipsilateral to the injury in 66.7% of the animals. The restored activity was far greater than that achieved via the same treatment applied acutely post SCI … Indeed, the combination treatment promoted coordinated motor activity indistinguishable from normal respiration.”

Getting the balance of IH therapy right was critical, however. Too much respiratory therapy resulted in abnormal electrical activity in the diaphragm. The researchers reason that this may be why the body releases inhibitory molecules to prevent the restoration of functional axons in the spinal cord. They are now working to optimize the treatment to help maximize recovery, particularly in the forearm.

Encouragingly, the improvements were still evident in animals a year and a half after therapy. “This is the first illustration that persistent, complete functional restoration in any motor system is possible well over a year following SCI,” the team wrote. “Our data illustrate the relative ease with which an essential motor system can regain functionality months to years after severe spinal cord injury,” commented Dr. Silver. “The treatment regimen in our study is relevant to multiple types of chronic incomplete spinal traumas, and we are hopeful it may also help restore motor function following spinal cord injury in humans.”

 

 

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