Scientists find drug that restores mice's ability to walk - Xinhua

WASHINGTON, July 19 (Xinhua) -- Researchers at Boston Children's Hospital showed that a small-molecule compound could revive neural circuits in paralyzed mice, restoring their ability to walk, according to a study published on Thursday in the journal Cell.

"For this fairly severe type of spinal cord injury, this is most significant functional recovery we know of," said He Zhigang in Boston Children's F.M. Kirby Neurobiology Center. "We saw 80 percent of mice treated with this compound recover their stepping ability."

Inspired by the success of epidural electrical stimulation-based strategies, He and colleagues applied an electric current to the lower portion of the spinal cord. Combined with rehabilitation training, it had enabled some patients to regain movement.

"Epidural stimulation seems to affect the excitability of neurons," said He. "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."

Then, He's team selected a handful of compounds that are already known to alter the excitability of neurons, and are able to cross the blood-brain barrier.

One compound called CLP290 showed the most potent effect, enabling paralyzed mice to regain stepping ability after four to five weeks of treatment.

Electromyography recordings showed that the two relevant groups of hindlimb muscles were active, and the animals' walking scores remained higher than the controls' up to two weeks after stopping treatment. Side effects were minimal.

CLP290 is known to activate a protein called KCC2, found in cell membranes, that transports chloride out of neurons.

The new study showed that inhibitory neurons in the injured spinal cord are crucial to recovery of motor function.

After spinal cord injury, these neurons produce dramatically less KCC2. As a result they can't properly respond to inhibitory signals from the brain, instead respond only to excitatory signals that tell them to keep firing.

Since these neurons' signals are inhibitory, the result is too much inhibitory signaling in the overall spinal circuit. Therefore, the brain's commands telling the limbs to move aren't relayed.

By restoring KCC2 with CLP290, the inhibitory neurons can again receive inhibitory signals from the brain, so they fire less.

This shifts the overall circuit back toward excitation, the researchers found, making it more responsive to input from the brain. This had the effect of reanimating spinal circuits disabled by the injury.

"Restoring inhibition will allow the whole system to be excited more easily," said He. "Too much excitation not good, and too much inhibition is not good either. You really need to get a balance."

He and colleagues are now investigating other compounds that act as KCC2 agonists. They believe such drugs, or perhaps gene therapy to restore KCC2, could be combined with epidural stimulation to maximize a patient's function after spinal cord injury.