Restoration of axonal conduction by potassium channel blocker
Most axons in the vertebral central nervous system are myelinated by oligodendrocytes. Myelin protects and insulates neuronal processes, enabling the fast, saltatory conduction unique to myelinated axons. It is well established that the increase of potassium channel activity is an important mechanism of conduction failure in spinal cord injury and multiple sclerosis. Suppressing aberrant potassium current by potassium channel blockade is an effective intervention for restoring signal conduction in demyelinated axons. Our lab has been involved in the original development of 4-aminopyridine, a well known potassium channel blocker that has seen recent clinical success as a treatment for multiple sclerosis symptoms. However, the narrow therapeutic range and the common side effects associated with its use limit the clinical application of 4-AP. In an effort to identify new compounds that could serve as viable alternatives to 4-AP, but perhaps with stronger effects and less side effects, We have identified several new compounds posses efficacy in restoring action potential conduction in injured axons. One of these potassium channel blockers, 4-AP-3-MeOH, was more potent than 4-AP. Furthermore, the derivative-rescued axons conduct electric impulses in a manner that is more like healthy axons than under 4-AP treatment. Therefore, these new derivatives are potential alternatives to 4-AP treatment in reversing conduction block in spinal cord injury and other demyelinating diseases. At the present time, 4-AP remains under study for use with spinal cord injury patients: blocking potassium channels remains a viable strategy in restoring axonal conduction and improving overall neurological function. Further studies of potassium blockade therapies for demyelinating diseases are warranted, as 4-AP has been approved for improving ambulatory ability in multiple sclerosis patients.
Selected publications related to the topic:
Shi, R. and Blight, A.R. The differential effects of low and high concentrations of 4-aminopyridine on axonal conduction in normal and injured spinal cord. Neuroscience 77:553-562, 1997.
Shi, R., Kelly, T.M. and Blight, A.R. Conduction block in acute and chronic spinal cord injury: different dose response characteristics for reversal by 4-aminopyridine. Exp. Neurol. 148: 495-501, 1997
Jensen, J.M. and Shi, R. Effects of 4-aminopyride on stretched mammalian spinal cord: The role of potassium channels in axonal conduction. J. Neurophysiol. 90: 2334-2340, 2003.
Smith, D. T., Shi, R, Borgens, R. B., McBride, J., Jackson K. and Byrn, S. B. Development of Novel 4-Aminopyridine Derivatives as Potential Treatments for Neurological Injury and Disease. European J. Med. Chem., 40: 908-917. 2005.
McBride, J. M., Smith, D. T., Byrn, S. R., Borgens, R. B. and Shi, R. Dose responses of three 4-aminopyridine derivatives following spinal cord trauma. European j. Pharmaceut. Sci. 27: 237-242. 2006.
Sun, W., Smith, D., Bryn, S., Borgens, R, and Shi, R. N-(4-pyridyl) methyl carbamate inhibits fast potassium currents in guinea pig dorsal root ganglion cells. Journal of Neurological Sciences. 277: 114-118. 2009.
Sun, W., Smith, D., Fu, Y., Cheng, J., Bryn, S., Borgens, R. and Shi, R. "A novel potassium channel blocker, 4-AP-3-MeOH, inhibits fast potassium channels and restores axonal conduction in injured guinea pig spinal cord white matter." Journal of Neurophysiol. 103: 469-478. 2010.
Leung, G., Sun , W., Brookes, S, Smith, D., Shi, R. Potassium channel blocker, 4-Aminopyridine-3-Methanol, restores axonal conduction in spinal cord of an animal model of multiple sclerosis. Experimental Neurology 227:232-235, 2011.
Shi, R. and Sun W. Potassium channels blockers as effective treatment to restore impulse conduction in injured axons (invited review). Neuroscience Bulletin. 27: 36-44, 2011.