Researchers at Boston Children’s Hospital have conducted a study that shows new insight as to why people with spinal cord injuries become paralyzed from the injury site down, even when the spinal cord has not become completely severed. Using paralyzed mice, they have shown that a small molecule compound when given systemically can revive these circuits and restore their ability to walk. They saw 80% of mice treated with the compound recover their stepping ability.

The researchers took a new approach from earlier studies which was inspired by the success of epidural electrical stimulation based strategies, the only treatment that was effective in treating patients with spinal cord injury. The treatment applied a current to the lower portion of the spinal cord and combined with rehabilitation training enabled some parties to regain movement. The epidural stimulation seemed to affect the excitability of neurons. When the stimulation was turned off, the effect was gone. The researchers tried to find a pharmacologic approach to mimic the stimulation and understand how it works.

The researchers selected a handful of compounds already known to alter the excitability of neurons and able to cross the blood brain barrier. The compound was given to mice in groups of 10 by intraperitoneal injection. All the mice used in the study had spinal cord injuries but with some nerves still intact. Each group including a control group that was given a placebo were treated for 8 to 10 weeks.

One of the compounds used, called COP290, had the most potent effect. It enabled paralyzed mice to regain stepping ability after 4 to 5 weeks of the treatment. Electromyography recordings showed that the 2 relevant groups of hind limb muscles were active. And the walking scores remained higher than the control groups up to 2 weeks after stopping treatment and side effects were minimal.

CLP290 is known to activate a protein called KCC2 which is found in cell membranes and transports chloride out of neurons. The current research shows that inhibitory neurons in an injured spinal cord are crucial to the recovery of motor function. These neurons produce drastically less KCC2 after a spinal cord injury and they are unable to properly respond to signals from the brain. They only respond to excitatory signals which tell them to keep firing. This results in too much inhibitory signaling in the overall spinal circuit. In other words, the brain’s commands telling the limbs to move aren’t relayed.

Restoring KCC2 with either genetic techniques or CLP290, the inhibitory neurons can receive inhibitory signals from the brain which tells them to fire less. The researchers found that this shifts the overall circuit back toward excitation making it more responsive to brain input. This had the same effect of reanimating spinal circuits which were disabled due to injury. By restoring inhibition, the whole system will be excited more easily. However, there does need to be a balance as too much excitation is not good and too much inhibition is not good either.

The team is now investigating other compounds that will act as agonists to KCC2. They believe such gene therapy to restore KCC2 might be combined with epidural stimulation to maximize function after spinal cord injuries.

To view the original scientific study click here: Reactivation of Dormant Relay Pathways in Injured Spinal Cord by KCC2 Manipulations

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