Protection of Neurological Function

Degeneration of axons is the primary cause for non-remitting abnormalities, and for permanent disability in MS and SCI. Our goal is to protect axons from degeneration and thus prevent irreparable loss of neurological function. To that end, and having previously demonstrated that an abnormal flooding of calcium into the axons, triggered by sodium influx via sodium channels ultimately leads to axonal degeneration, we studied the effects of sodium channel blockers on disease progression in the rodent EAE model of MS.

In our previous studies, we used the sodium channel blocker phenytoin, an anticonvulsant drug that is currently in clinical use for the treatment of epilepsy. Upon treating the EAE animals with phenytoin, we found that nearly ninety percent of the optic nerve axons-the fibers that transmits signals between the eye and the brain-remained intact compared to less than fifty percent in untreated animals (Lo et al., 2002, NeuroReport).

We then extended these studies to demonstrate a significant protection of nerve fibers that control motor function within the spinal cord by treating EAE animals with phenytoin (Lo et al., 2003, Journal of Neurophysiology). The clinical status as indicated by a score of 1.5 compared to 3.3 in untreated animals, also improved substantially in phenytoin treated EAE animals. In other words, the rate at which the disease progressed was much slower in phenytoin treated animals compared to those that were left untreated.

We also studied protection of axons in animal models following experimental contusion SCI. Our studies are the first to demonstrate that administration of phenytoin after SCI not only provides substantial protection of both white and gray matter surrounding the injury site, but also promotes motor recovery and recovery of fine motor control in injured animals (Hains BC et al., 2004).

These findings have important implications in the development of treatments for MS and SCI using phenytoin to potentially delay or prevent further nerve damage. We now hope to replicate these experiments in a Phase II clinical study of neuroprotection in humans with MS, with the goal of developing neuroprotective treatments that will also prevent further loss of neurological function in people with SCI.

Lo AC, Saab CY, Black JA, Waxman SG. Phenytoin protects spinal cord axons and preserves axonal conduction and neurological function in a model of neuroinflammation in vivo. J Neurophysiol. 2003 Nov; 90(5):3566-71. Epub 2003 Aug 06.

Hains BC, Saab CY, Lo AC, Waxman SG. Sodium channel blockade with phenytoin protects spinal cord axons, enhances axonal conduction, and improves functional motor recovery after contusion SCI. Exp Neurol. 2004 Aug; 188(2):365-77.

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