SCIRP 2012 Investigator Vignette

Title: Improving Transmission in Damaged Spinal Cord to Promote Recovery of Function After Spinal Cord Injury

Investigator: Victor Arvanian, PhD, DSi; Northport Veterans Affairs Medical Center

So the outline of this grant is that the most of spinal cord injuries are incomplete anatomically. It means that there are lots of fibers remaining after the injury, the intact fibers. However, almost all injuries are complete functionally; meaning that below the level of injury there is no sensation and motor function below this level of injury.

In order to understand why these surviving fibers cannot mediate better recovery, we did electro-physiological experiments in which we evaluated physiological conditions of these fibers. And we found that immediately after the injury these surviving fibers can transmit to motor neurons. However, there is a pronounced reduction in transmission through the surviving fibers after a couple days after the injury. And what is important is that initiation of this physiological and behavioral deficit, coincided with the time whether elevation of scar-related molecules, which are chondroitin sulfate proteoglycans, so called CSPGs, in tissues was maximum.

CSPGs are an essential component of so-called perineuronal net and they're always there. They are present in CNS. However, the levels of the CSPGs are pretty low. Now after the injury when the glio-scar is forming, there is a robust accumulation of CSPGs in the vicinity of the injury.

So in our studies we decided to examine if the CSPGs with levels elevated after the injury could block transmission to motor neurons.

We recorded intracellularly from individual motor neurons in lumbar section of the cord. And responses in this motor neuron were evoked by electric stimulation of the descending fibers at the thoracic level. And normal, noninjured threads were found that these responses are pretty large. However, after partial injury conduction in the spared fibers in the caudal region was impaired. And you can see that the CSPGs are very small.

So we used enzymes, so-called chondroitinase ABC, which is known to digest CSPGs to see if digestion of CSPGs could recover transmission. And we found that transmission could be partially recovered. This means that CSPGs are really involved in the block of conduction of the chronic partial spinal cord injury.

Now the problem with treatment with enzyme is that it's not selective; it pretty much dissects all CSPGs.

Our philosophy was that if CSPGs are coming to the injury they might be useful to the injury. It means that not all CSPGs might be bad; maybe some CSPGs could be useful. And that's why we examined how these individual CSPGs could affect conduction. And we found that one CSPG, which is NG2, induced block of the "CPS-piece." The other CSPGs that we examined did not.

It means that NG2 is inducing conduction block at the spinal cord injury. So using funds from DoD, we begun collaboration with Dr. Joel Levine, and Dr. Joel Levine actually is an expert in NG2; he discovered this NG2 molecule. And moreover he created an antibody against this NG2. So we are using NG2 that was created in his laboratory, and we're investigating the effect of NG2 antibody in our spinal cord injury model.

In this model of the section of this spinal cord injury, when one side of the cord is completely lesion(ed) and the other side remains intact, in noninjured thread you can see that the signal is pretty big. After a hemi-section injury, the signal is decreased. However, in the rats that have been treated with NG2 neutralizing antibody, we have partial recovery of the signal. So this means that treatment with NG2 antibody improves not only transmission in the damaged spinal cord but it improves anatomical plasticity in the damaged spinal cord.

So our next step will be to combine this treatment that we found which is beneficial with other treatments which we have discovered before to be beneficial. So we got some preliminary results and we hope that we will get funding during the next period, and we'll try to complete the next set of experiments.