Potassium channel blockers as an effective treatment to restore impulse conduction in injured axons

Abstract

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. Myelin disruption resulting from trauma and biochemical reaction is a common pathological event in spinal cord injury and chronic neurodegenerative diseases. Myelin damage-induced axonal conduction block is considered to be a significant contributor to the devastating neurological deficits resulting from trauma and illness. Potassium channels are believed to play an important role in axonal conduction failure in spinal cord injury and multiple sclerosis. Myelin damage has been shown to unmask potassium channels, creating aberrant potassium currents that inhibit conduction. Potassium channel blockade reduces this ionic leakage and improves conduction. The present review was mainly focused on the development of this technique of restoring axonal conduction and neurological function of demyelinated axons. The drug 4-aminopyridine has recently shown clinical success in treating multiple sclerosis symptoms. Further translational research has also identified several novel potassium channel blockers that may prove effective in restoring axonal conduction.

Structure, Molecular Modeling, and Function of the Novel Potassium Channel Blocker Urotoxin Isolated from the Venom of the Australian Scorpion Urodacus yaschenkoi

“…Additionally, a simulation with mutant-urotoxin (Lys25Ala) indicated that Lys25 does not have the same role in the binding of urotoxin to hK v 1.2 as in other a-KTx-6 toxins. Our results suggest that urotoxin may be useful as a pharmacologic tool to reveal the physiologic function of hK v 1.2 channels in in vitro and in vivo experiments, as a lead for peptidomimetics for the targeting of hK v 1.2 channels, and as an experimental therapeutic tool to restore axonal conduction in demyelinated axons, where inhibition of K 1 channels has beneficial effects (Beraud et al, 2006;Shi and Sun, 2011).…”

“…Knowledge of the interacting surfaces between the channels and toxins may allow the design of specific drugs to control pathologies associated with K 1 channels, such as demyelinating diseases (e.g., Guillain-Barré syndrome, multiple sclerosis) and Lambert-Eaton myasthenic syndrome (Judge and Bever, 2006;Shi and Sun, 2011).…”

Molecular mechanisms of acrolein-mediated myelin destruction in CNS trauma and disease

“…Myelin enhances axonal conduction by both inhibiting ionic exchange across the membrane and increasing transverse resistance at the internodal region [12]. Accordingly, compromise of the structural integrity of myelin elicits significant conduction loss in spinal cord tissue partly due to the exposure and consequential activation of voltage-gated K + channels typically residing in the juxtaparanodal region [1, 10, 11, 13–15]. Ex vivo studies of spinal cord tissue have demonstrated that myelin damage and subsequent exposure of K + channels impaired signal propagation, indicated by a reduction of compound action potential (CAP) amplitude [10, 11, 14].…”

“…In the case of trauma, primary injury mediated by physical forces triggers subsequent pathological molecular mechanisms, deemed secondary injury [22, 23]. Separation of these two components was postulated decades ago and has been supported by many subsequent studies [13, 22, 23]. Recently, this phenomenon was demonstrated in an ex vivo acute spinal cord injury model where a mechanical stretch injury resulted in immediate myelin damage indicated by lengthening of the nodal region and retraction of myelin from the paranodal region following the physical insult [11].…”

Optic nerve regeneration in mammals: Regenerated or spared axons?

“…These studies have raised a possibility that neuronal tracers may fail to fully illuminate those damaged (but structurally connected) axons, at least transiently and during the early phase of injury, potentially confounding the use of serial labeling approaches to argue for regeneration. Others have reported that surviving but compressed axons may also be physiologically abnormal for a certain period of time, probably due to altered myelin structure and potassium channel activity, leading to conduction failure and loss of function (Nashmi & Fehlings, 2001; Shi & Sun, 2011). …”