The mechanism and treatment for myelin damage in central nervous system trauma and diseases

Wenjing Sun, Purdue University

Abstract

The present study is focused on investigating the mechanism of myelin damage in spinal cord injury and multiple sclerosis. In addition, potential treatments are explored to either restore conduction through demyelinated axons or provide neuroprotection. Mechanical injury causes myelin disruption and subsequent axonal conduction failure in mammalian spinal cord. However, the underlining mechanism is not well understood. In mammalian myelinated axons, proper paranodal myelin structure is crucial for the generation and propagation of action potentials by restricting the potassium channels under the myelin. Exposure of potassium channels due to injury is thought to short circuit depolarization and derails the genesis of action potential, leading to conduction failure. In the first part of the current study we used multimodal imaging techniques and provided unequivocal anatomical evidence demonstrating paranodal myelin disruption and consequential exposure and redistribution of potassium channels following mechanical insult in guinea pig spinal cord. It is shown that paranodal demyelination can result from initial physical impact and secondary biochemical reactions that are calcium dependent. 4-aminopyridine (4-AP), a known potassium channel blocker can partially restore axonal conduction, which further implicates the role of K+ channels in conduction failure. We also show that acrolein, a lipid peroxidation product, can cause significant myelin damage in isolated guinea pig spinal cord segments. Acroleinmediated myelin damage is particularly conspicuous in the paranodal region in both a calcium dependent (nodal lengthening) and a calcium-independent manner (paranodal myelin splitting). In addition, paranodal protein complex is dissociated with acrolein incubation. Degraded myelin basic protein is also detected at paranodal region. Acrolein-induced exposure and redistribution of paranodal potassium channels and resulting axonal conduction failure can be partially reversed by 4-AP. It is suggested that acrolein toxicity is partially mediated by calpain. We have demonstrated that 4-AP-3-MeOH, a 4-aminopyridine derivative, significantly restored axonal conduction in stretched spinal cord white mater strips, and showed no preference in restoring large and small axons. This compound is10 times more potent than 4-AP and other derivatives in restoring axonal conduction. Unlike 4-AP, 4-AP-3-MeOH can restore axonal conduction without altering axons’ ability to respond to dual or multiple stimuli. In addition, we have also confirmed that 4-AP-3-MeOH effectively blocks IA based on patch clamp studies using guinea pig dorsal root ganglia cells. Multiple sclerosis (MS) is a severely debilitating neurodegenerative diseases and the mechanism by which it occurs is not completely clear yet. To study multiple sclerosis, we used a well established animal model experimental autoimmune encephalomyelitis (EAE) mouse. Our results showed that 4-AP-3-MeOH can significantly increase axonal conduction in ex vivo EAE mouse spinal cord. We have also demonstrated a significant elevation of acrolein protein adduct levels in EAE mouse spinal cord. Hydralazine, an acrolein scavenger, significantly improved behavioral outcomes and lessened myelin damage in spinal cord.

Degree

Ph.D.

Advisors

Shi, Purdue University.

Subject Area

Neurosciences|Pathology

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