Scientists restore breathing and forelimb function in animal models of chronic spinal cord injury

Millions of people around the world live with chronic spinal cord injuries, with 250,000 to 500,000 new cases each year, mostly road crashes or falls. The most serious spinal cord injuries completely paralyze their victims and more than half compromise their ability to breathe. Now, a breakthrough study published in Nature Communications has demonstrated in animal models of chronic lesion that the long-term devastating effects of spinal cord injury on limb respiration and function may be reversible.

The new study describes a treatment regimen that can wake up certain particular types of nerve cells that can regenerate extensions, called axons, within the damaged spinal cord. Rats whose spinal cord was cut halfway at the second cervical vertebra (C2) found the complete diaphragm and partial function of the forelimb after treatment. The recovery effects of treatment were fully maintained six months after the end of treatment.

"For the first time, we have permanently restored both breathing and certain arm functions in a form of elevated cervical paralysis caused by chronic spinal cord injury," says lead author Jerry Silver, PhD, professor of Neuroscience at the Faculty of Medicine at Case Western Reserve University.

The treatment exploits the body's innate ability to germinate very slowly new axon branches from a subpopulation of nerve cells that remain intact beneath the lesion. The activity of these new branches is completely stifled by a family of powerful inhibitory molecules called proteoglycans. Silver said: "The strategy was to use a single single injection of an enzyme, chondroitinase, which breaks down the inhibitory molecules of proteoglycan.The enzyme was administered not in the lesion itself, but in the resident nerve cells that send the axons to the diaphragm and forearm. "

In animals treated immediately after spinal cord injury, the enzyme contributed only marginally to restore nerve growth with minimal functional recovery. However, in animals treated long after the injury, the therapeutic effects of the enzyme were remarkably better. Just one week after treatment in rats with chronic lesions, new nerve extensions began to restore the function of the diaphragm, which had remained silent for several months. Seventy percent of chronically treated rats with the enzyme also started using their forelimbs to move and explore their environment (compared to only 30% of control animals).

"Surprisingly, the technique worked much better in the chronic stages than in acute stages after an injury," says Silver. The longer the animals were paralyzed, the more restorative effects of the enzyme were important. The Silver team found that even after an unprecedented year and a half after a spinal cord injury, the treatment could regain full activity at the rat's diaphragm. One week after treatment, 60% of the animals showed an improvement in the function of the diaphragm. Two weeks later, all the rats showed improvement, even though their paralysis lasted most of their lives.

Interestingly, exposing rats to brief periods of lack of oxygen, a respiratory therapy known as intermittent acute hypoxia, has helped to reinforce growing nerve extensions, thus offering an added benefit. However, Silver's team found that when rats were treated with the enzyme associated with excessive amounts of respiratory treatment, they developed a chaotic activity in their formerly paralyzed diaphragms. The researchers hypothesized that the potential for extremely abnormal activity could be the reason why the body releases inhibitory molecules in order to prevent the functional regeneration of axons in the spinal cord. They are currently working on optimizing the association treatment to maximize recovery, especially in the forearm and paw.

"Our data illustrates the relative ease with which an essential motor system can regain functionality from months to years after a serious spinal cord injury," says Silver. "The treatment regimen of our study is suitable for many types of incomplete chronic spinal cord injury and we hope that it will also help restore motor function following a spinal cord injury in the elderly." 39, man. "