Novel potassium channel blocker, 4-AP-3-MeOH, restores axonal conduction in acrolein-damaged rat spinal cord axons

Rui Yan, Purdue University

Abstract

Multiple sclerosis (MS) is a severe neurodegenerative disease signified by motor impairment caused by conduction block of demyelinated axons in the central nervous system. The mechanism of axonal conduction loss is believed to be largely due to the exposure of potassium channels resulting from myelin damage and increasing outward current. Consistent with this notion, potassium channel blockers are known for restoring conduction in the demyelinated axons. Consequently, such treatment has been identified as a key therapeutic strategy to restore function in MS. In the current study, we have established an ex vivo rat spinal cord axonal demyelination model produced by acute exposure of acrolein which has been linked to myelin damage in MS. Using a well-established double sucrose gap recording system, acrolein was applied to isolated strips of spinal cord to induce acrolein-mediated functional loss by monitoring compound action potential (CAP) conductance. The current study demonstrates that acrolein can lead to the reduction of CAP amplitudes, providing direct evidence supporting the role of acrolein in spinal cord injury. We also confirm the acrolein-mediated myelin damage via morphological evaluation such as plastic section taken from the acrolein-exposed spinal cord. We have further shown that a novel potassium channel blocker, 4-AP-3-MeOH can restore axonal conduction in acrolein-damaged axons due to the enhancement of CAP. The degree of improvement in axonal conduction by 4-AP-3-MeOH is significant and comparable to that induced by the bench mark potassium channel blocker 4-AP in similar preparation. While 4-AP is an FDA-approved medication to improve walking ability in MS patients, its narrow therapeutic range and significant side effects limit its effectiveness in clinical application. Previous studies have indicated that unlike 4-AP, 4-AP-3-MeOH can restore axonal conduction without adversely changing electrophysiological properties. In addition, 4-AP-3-MeOH is 10 times more potent than 4-AP in restoring axonal conduction. Therefore, 4-AP-3-MeOH is likely a viable alternative for MS patients in which 4-AP treatment is ineffective.

Degree

M.S.

Advisors

Shi, Purdue University.

Subject Area

Neurosciences

COinS