Rats with severe spinal cord injury were able to urinate normally after scientists used a new technique to regenerate nerve cells across the site of injury. The US team hopes their methods will help develop treatments that restore bladder function in humans with severe spinal cord injuries, and also guide efforts to restore other functions.
Yu-Shang Lee, of the Cleveland Clinic, and Jerry Silver, of Case Western Reserve Medical School, both in Cleveland, Ohio, and others, write about their work in a new study due to be published in Wednesday’s online issue of The Journal of Neuroscience.
In a statement, Lee says:
“This is the first time that significant bladder function has been restored via nerve regeneration after a devastating cord injury.”
“Although animals did not regain the ability to walk, they did recover a remarkable measure of urinary control,” says Silver.
Being able to urinate again would bring a huge improvement to the quality of life for people with severe spinal cord injuries. Many patients rate it as one of the most important functions to regain following injury.
Paralyzed rats’ bladders leak urine when they are full, but this doesn’t happen in paralyzed humans: instead, the urine backs up into the kidneys. Without a catheter this would lead to kidney failure and eventually death.
Following a spinal cord injury, the extensions of nerve cells from the brainstem are disconnected from nerve cells in the spinal cord. This means the brain signals that control and coordinate urination don’t reach the nerve cells that control the muscles that squeeze the bladder and open and close the urethra.
The body’s natural response to the trauma is to limit the inflammation by causing scar tissue to form at the site of injury. While this protects the victim’s body from further damage, it ruins the chance of restoring nerve function.
Cells in the scar tissue release molecules that stop the nerve fibers from growing past the site of damaged tissue, so they cannot reconnect with each other, resulting in permanent inability to empty the bladder.
For years, Silver and the team have been perfecting an approach that removes the scar tissue and encourages the damaged nerve cells to regrow.
They take healthy nerves from another part of the rats’ bodies, graft them onto a damaged area of spinal cord and add two chemicals: one that promotes cell growth, and another that disrupts scar formation to create a more hospitable environment for the nerve cells to grow across the site of injury.
In 2011 they reported how this technique restored breathing in paralyzed rats.
In the current study, the researchers used an enzyme called chondroitinase to disrupt scar formation, and a fibroblast growth factor to promote cell survival while they carried out the nerve graft surgery at the site of injury.
They used seven groups of rats. One group had a small portion of a vertebral bone removed (the sham or control group whose injury did not result in paralysis). The other groups all received cuts to the spinal cord rendering them paralyzed but then received either no treatment or various combinations of treatment (eg graft but no chemicals, or graft and only one chemical, or chemicals but no graft).
They then monitored the rats’ urine output three to six months later. As expected the paralyzed rats that received no treatment had the lowest urine output and the group that had the sham surgery (not paralyzed) had the highest.
All the paralyzed rats that received some form of treatment had improved bladder function at three and six months compared to the paralyzed rats that received no treatment. But the group that received the graft plus the growth factor chemicals and the scar-busting chemical showed the most improvement.
The researchers also saw the regrowth of some brainstem cells across the injury site.
Silver says they were especially surprised and excited to see that a subset of nerve cells located mostly in the brainstem could slowly regrow far down the spinal cord once they had a more hospitable environment that allowed them past the site of the scar.
“What endows these particular neurons with such an innately high re-growth capacity is unknown but will be an extremely important area of research in the future,” he adds.
While the study is a significant step forward, there are still more challenges ahead before this type of approach can be tested in people, warns Elizabeth Bradbury, a spinal cord injury researcher at King’s College London who did not take part in the study.
“Nevertheless, this remarkable advance offers great hope for the future of restoring bladder function to spinal cord injury patients,” she adds.
Grants from the National Institute of Neurological Disorders and Stroke and the Cleveland Clinic Foundation helped pay for the study.
In 2012, scientists suggested that chondroitinase and other scar-busting enzymes may also have potential use for improving outcomes in chronic stroke.
Written by Catharine Paddock PhD