Researchers Develop Novel Drug to Reactivate Dormant Nerve Pathways


Researchers from Boston Children’s Hospital developed a new drug that can revive dormant nerve circuits in paralysis to restore the ability to walk.

A spinal cord injury in most people leads to paralysis from the injury site down, even when the cord is not completely severed. Now, researchers at Boston Children’s Hospital identified the mechanism that causes the nerve pathways to remain nonfunctional. In a paper published in the journal Cell on July 19, 2018, the researchers suggest that a small-molecule compound can revive these circuits in paralyzed mice, restoring their ability to walk.

The researchers analyzed several already known compounds that alter the excitability of neurons and cross the blood-brain barrier. Each of these compounds were tested on paralyzed mice in groups of 10 via intraperitoneal injection. All mice in the experiment suffered from severe spinal cord injury. However, some nerves in these mice were still intact. The researchers observed that one compound, called CLP290, showed significant effects as it enabled paralyzed mice to regain stepping ability after four to five weeks of treatment. CLP290 is known to activate a protein called KCC2 that transports chloride out of neurons. These inhibitory neurons are crucial for the recovery of motor function in the injured spinal cord. An injury in the spinal cord leads to less production of KCC2, which in turn decreases its ability to respond to signals from the brain. The inability of processing inhibitory signals suggests CLP290 to keep firing due to the responses from excitatory signals. Furthermore, too much inhibitory signaling in the overall spinal circuit leads to breaking of the brain’s commands suggesting the limbs to move. The researchers observed that restoring KCC2, with either CLP290 or genetic techniques can restore the ability of the inhibitory neurons to receive inhibitory signals from the brain, which in turn will command them to fire less. This restoration excites the overall circuit, which makes it more responsive to input from the brain and eventually reanimate spinal circuits disabled by the injury.


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