Paralyzed mice regain movement in their legs with new treatment

The drug reactivates nerve pathways in partially severed spinal cords.

Most people with spinal cord injuries are paralyzed below the injury site, even if the cord is only partially severed. Researchers don’t know why the nerve pathways that are still intact also stop working. A new study provides a promising answer, and a path to restoring movement.

Researchers treated mice with partially severed spinal cords with a compound called CLP209. The drug was administered over eight to ten weeks. About 80 percent of the injured mice regained their ability to take steps. “Stepping is a first step towards motor functional recovery in animals, and perhaps humans,” says Boston Children’s Hospital researcher Zhigang He, who led the study.

A new approach is paying off


Many animal studies attempting to repair spinal cord damage have focused on getting nerve fibers to regenerate, or new ones to grow out of remaining healthy fibers. He and other researchers have achieved this, but they didn’t see the corresponding improvements in motor function they had hoped for.

He and his coauthors decided to try a different approach. They were inspired by treatments that stimulate the space around injured patients’ spinal cord with electric currents. When combined with rehabilitation training, this stimulation is the only treatment for spinal cord injury patients known to be effective. "However, in these studies, when you turn off the stimulation, the effect is gone,” says He.

The researchers set out to see if they could use drugs to mimic the stimulation caused by electric currents, so the effect would be longer-lasting. They tested several compounds known to alter the excitability of neurons. A small molecule called CLP209 worked best, and the treated mice remained more mobile than untreated mice up to two weeks after treatment stopped.

Results explain why remaining nerve pathways don’t function normally


The fact that CLP209 worked so well gives researchers a major clue as to why even intact nerve pathways fail after a spinal cord injury. The key seems to be a protein called KCC2, which CLP290 is known to activate.

To facilitate movement like walking, the spinal cord transmits the brain’s commands to muscles with two types of signals: those that inhibit muscles’ neurons and those that activate them. These opposing signals are what allow muscles to work in pairs, with one relaxing while the other contracts.

After a spinal cord injury, neurons that send signals inhibiting movement don’t produce enough of the KCC2 protein. As a result of this deficit, they don’t receive instructions from the brain to stop firing, and the overall spinal circuit is overwhelmed with inhibitory signals.

When the mice were treated with CLP290, the drug restored KCC2 levels, the brain’s commands to stop firing got through to inhibitory neurons, and signals resulting in movement were no longer overpowered.

"Too much excitation is not good, and too much inhibition is not good either,” says He. “You really need to get a balance. This hasn't been demonstrated in a rigorous way in spinal cord injury before."

 

A cross section of a mouse spinal cord, stained two different ways, showing increased expression of KCC2 in inhibitory neurons. Credit: Zhigang He Lab, Boston Children's Hospital

More research is needed to determine the treatment’s full potential


He and his colleagues are now exploring other drugs to activate KCC2 in spinal cord injuries. They hope their therapy could one day be combined with electrical stimulation techniques to maximize patients’ recovery.

They also hope they won’t be alone in exploring this type of drug’s potential. He says: “It would be great if other groups are willing to try this in their injury models. We hope that collectively we could find out the strengths and weaknesses of this approach and consider which patient populations could be targeted.”

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