Research from WorldCare Consortium™ member Boston Children’s Hospital shows insight and promise for treatment of paralyzing spinal cord injuries
A new study from WorldCare Consortium™ member Boston Children’s Hospital provides insight into why non-damaged portions of spinal cord frequently don’t permit movement below the actual site of spinal cord injury in patients. In addition, the study shows that injection with a small-molecule compound can revive these circuits in paralyzed mice, allowing them to walk again.
Animal studies looking to repair spinal cord damage have usually focused on getting nerve fibers, or axons, to regenerate, or getting new axons to sprout from healthy ones. This new study took a different approach, which could complement previous strategies with researchers noting that epidural electrical stimulation, which applies a current to the lower portion of the spinal cord, has enabled some patients to regain movement in combination with rehabilitation training. So far, this is the only clinical treatment that’s been found effective.
“Epidural stimulation seems to affect the excitability of neurons,” stated Zhigang He, PhD, senior investigator at F.M Kirby Neurobiology Center at WorldCare Consortium™ member Boston Children’s Hospital. “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.”
Researchers selected a handful of compounds already known to alter the excitability of neurons and are able to cross the blood-brain barrier, giving each compound to paralyzed mice, who had severe spinal cord injury with some nerves still intact, in groups of 10 by intraperitoneal injection. One compound, CLP290, had the most potent effect, allowing paralyzed mice to regain stepping ability after four to five weeks of treatment. Electromyography recordings indicated that the two relevant groups of hindlimb muscles were active, and the animals’ walking scores remained higher than the controls’ two weeks after stopping treatment, with minimal side effects.
Research findings show that inhibitory neurons in the injured spinal cord are crucial to recovery of motor function. CLP290 is known to activate a protein called KCC2, which is found in cell membranes and transports chloride out of neurons. After a spinal cord injury, inhibitory neurons drastically produce less KCC2, making these neurons unable to properly respond to inhibitory signals from the brain, with commands from the brain telling the limbs to move not being relayed. By restoring KCC2, either with CLP290 or genetic techniques, inhibitory neurons can again process inhibitory signals from the brain, so they fire less, shifting the overall circuit back toward excitation and making it more responsive to input from the brain. This leads to the reanimation of spinal circuits disabled by injury. Researchers are now investigating other compounds that act as KCC2 agonists, with the belief that these drugs could be combined with epidural stimulation to maximize function after spinal cord injury, with gene therapy to restore KCC2 as another possibility.
“We are very excited by this direction,” explained He. “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.”
Journal Reference: Bo Chen, Yi Li, Bin Yu, Zicong Zhang, Benedikt Brommer, Philip Raymond Williams, Yuanyuan Liu, Shane Vincent Hegarty, Songlin Zhou, Junjie Zhu, Hong Guo, Yi Lu, Yiming Zhang, Xiaosong Gu, Zhigang He. Reactivation of Dormant Relay Pathways in Injured Spinal Cord by KCC2 Manipulations. Cell, 2018; DOI: 10.1016/j.cell.2018.06.005