As anyone might expect, spinal cord injuries are complicated, nuanced and somewhat mysterious. Most people who experience them are paralyzed from the site of the injury down, even if portions of their spinal cord remain intact. Now researchers at Boston Children's Hospital might be closer to learning why even un-severed nerve pathways stop functioning and the specific protocols that could actually help awaken these sleeping circuits and help injured people walk again.
A new study on mice led by Zhigang He, Ph.D., in Boston Children's F.M. Kirby Neurobiology Center, and published July 19, 2018 in the journal Cell, suggests an overlooked strategy could help restore movement for spinal cord injury patients. The study drew inspiration from epidural electrical stimulation-based strategies (the only known effective treatment for spinal cord injury), which involves applying a current to lower portions of the spinal cord, combined with rehabilitation training. While many animal researchers have prioritized regenerating nerve fibers (or axons), He and his colleagues took a different approach.
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"Epidural stimulation seems to affect the excitability of neurons," He said in a press release. "However, in these studies, when you turn off the stimulation, the effect is gone. We tried to come up with a pharmacologic approach to mimic the stimulation and better understand how it works."
The team's strategy involved several compounds that alter neuron excitability (known as agonists). The compounds were given to groups of mice that all had spinal cord injuries but retained some intact nerves. He and his colleagues studied the mice over eight to 10 weeks and found that one compound — CLP290 — had the most profound effect, and even enabled paralyzed mice to start taking steps again after just four to five weeks of treatment. The side effects from the treatment were minimal and researchers noted improvements in the walking scores of these mice compared to controls up to two weeks after treatment was stopped.
So what is CLP290? It's a compound that activates a protein found in cell membranes called KCC2 that's responsible for ushering chloride out of neurons. Based on this new research, it appears that neurons produce significantly less KCC2 after spinal cord injury, which subsequently affects their ability to respond to brain signals. He and his colleagues believe that by restoring KCC2, the neurons can regain the ability to receive the correct brain signals and potentially initiate restored movement.
The next step is to investigate whether other compounds can have this effect on KCC2 and whether treatments, including medications and gene therapy, could be combined with epidural stimulation to help spinal cord injury patients regain circuit functions.
"We are very excited by this direction," He said. "We want to test this kind of treatment in a more clinically relevant model of spinal cord injury and better understand how KCC2 agonists work."
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