Spinal cords of rats shown 24 hours after cervical injury. The rat whose spinal cord is shown in A...
Spinal cords of rats shown 24 hours after cervical injury. The rat whose spinal cord is shown in A received no active treatment whereas the rat whose spinal cord is shown in B was treated to suppress Abcc8, demonstrating a noticeable reduction in hemorrhage.
(Courtesy J. Marc Simard, M.D., Ph. D.)
Suppressing the gene for an ion flux regulatory molecule protected rats against paralysis following spinal cord injury, researchers said, a finding that could have similar implications in humans.
An antisense oligonucleotide, given intravenously 15 minutes after rats' spinal cords were crushed, improved trunk and hind-limb function compared with a sham treatment when the animals were tested six weeks later, according to J. Marc Simard, MD, PhD, of the University of Maryland in Baltimore, and colleagues.
The experiment was one of several implicating the Sur1 receptor protein, which helps control sodium and calcium fluxes into and out of cells, as being critical to loss of neuronal function after injury. The findings were reported online in Science Translational Medicine.
Simard and colleagues suggested that therapies targeting Sur1 expression, combined with glibenclamide (to block preexisting ion channels), appear to be "a promising strategy for prevention of the devastating sequelae of spinal cord trauma in humans."
Sur1 is shorthand for sulfonylurea receptor 1, a name denoting its original discovery as a target for some diabetes drugs.
It has never been clear why total paralysis frequently results when the human spinal cord is injured but not severed: the trauma evidently triggers processes that cause spinal neurons to die off or otherwise cease working over time.
As a result, researchers have been looking for ways to interrupt those process and salvage spinal cord function.
One of those nerve-killing processes appears to be the hemorrhaging that frequently follows a spinal injury, which results from a slow but catastrophic failure of capillaries around the injury site, according to Simard and colleagues.
Previous research indicated that expression of calcium channels regulated by Sur1 surges in capillary endothelial cells during these secondary hemorrhages and is at least partly responsible for them.
Simard and colleagues confirmed the importance of Sur1 in this process with tests on spinal cord tissue taken from human patients who died a few days after spinal trauma. Sur1 proteins were detected in penumbral tissues around the site of injury, but they were less common at the epicenter and absent in remote areas.
Messenger RNA associated with the gene for Sur1, Abcc8, was also more abundant in penumbral regions, but not farther away.
The researchers also studied the effects of spinal cord injury on mice whose Abcc8 gene was silenced and compared them with injuries to normal mice.
Relative to the normal animals, those with Sur1 expression that had been knocked down showed much less secondary hemorrhaging, and it reached its maximum extent within 30 minutes. In the normal mice, hemorrhaging and necrosis continued to spread for 24 hours.
In a final set of experiments, rats had their spinal cords crushed in a standardized way, and an antisense oligonucleotide was administered 15 minutes later, designed to block translation of Abcc8.
Five types of neuromotor function tests -- assessing the animals' trunk stability, walking and rearing ability, and balance after six weeks -- all showed performance "consistently better" in the treated animals than in rats given a nonsense oligonucleotide.
Simard and colleagues found that glibenclamide, a Sur1 antagonist, also improved rats' performance in the spontaneous rearing test following the same type of injury.
Both the antisense drug and glibenclamide led to 75% reductions in spinal cord lesion volume six weeks after the injury, compared with sham-treated animals, the researchers reported.
"Future studies will be needed to determine the therapeutic window for Abcc8 antisense as well as for Sur1 inhibitors such as glibenclamide," Simard and colleagues concluded.
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