Novel Potassium Channel Blocker, 4-AP-3-MeOH, Inhibits Fast Potassium Channels and Restores Axonal Conduction in Injured Guinea Pig Spinal Cord White Matter

Sun, Wenjing; Smith, Daniel T.; Fu, Yan; Cheng, Ji‐Xin; Bryn, Steven; Borgens, Richard B.; Shi, Riyi

doi:10.1152/jn.00154.2009

Cited by 41 publications

(78 citation statements)

References 51 publications

(18 reference statements)

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“…In a recent study, a finite element mathematical model suggested that mechanical compression would produce high stresses in the paranodal axonal-glial junction [19] . This is consistent with the reported observations that this region is vulnerable to mechanical injury [9,10] . Furthermore, it also confirms that mechanical deformation alone is sufficient to rupture the tight, septate junctions that join myelin to the axonal membrane.…”

supporting

confidence: 94%

“…Exposure of potassium channels in the juxtaparanodal region is believed to be the underlying mechanism of conduction block in demyelinated axons [9,10,19] . Under normal conditions, deplorization at the node of Ranvier will drive potassium ions down to the electrical gradient.…”

Section: Suggested Mechanisms Of 4-ap-mediated Restoration Of Axonal mentioning

confidence: 99%

“…However, the unique cellular structure that enables efficient saltatory conduction is vulnerable to mechanical insults which can lead to impulse conduction block. Specifically, myelin damage is associated with axonal conduction loss in trauma and chronic neurodegenerative diseases [3][4][5][6][7][8][9][10] . The mechanisms of myelin damage-induced axonal conduction loss have attracted much attention these years.…”

Section: Introductionmentioning

confidence: 99%

“…Neurosci Bull February 1, 2011, 27(1): [36][37][38][39][40][41][42][43][44] age in chronic mechanical trauma [4,20,[22][23][24]26,30] , acute trauma can also affect myelin [9,10,19] . Several studies have revealed myelin displacement immediately following mechanical insults such as stretch and compression [9,10,19] .…”

mentioning

confidence: 99%

“…Several studies have revealed myelin displacement immediately following mechanical insults such as stretch and compression [9,10,19] . In a recent study, a finite element mathematical model suggested that mechanical compression would produce high stresses in the paranodal axonal-glial junction [19] .…”

mentioning

confidence: 99%

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

Shi

Sun

2011

Neurosci. Bull.

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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.

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supporting

confidence: 94%

Section: Suggested Mechanisms Of 4-ap-mediated Restoration Of Axonal mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Shi

Sun

2011

Neurosci. Bull.

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From demyelination to remyelination: The road toward therapies for spinal cord injury

Papastefanaki

Matsas

2015

Glia

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Myelin integrity is crucial for central nervous system (CNS) physiology while its preservation and regeneration after spinal cord injury (SCI) is key to functional restoration. Disturbance of nodal organization acutely after SCI exposes the axon and triggers conduction block in the absence of overt demyelination. Oligodendrocyte (OL) loss and myelin degradation follow as a consequence of secondary damage. Here, we provide an overview of the major biological events and underlying mechanisms leading to OL death and demyelination and discuss strategies to restrain these processes. Another aspect which is critical for SCI repair is the enhancement of endogenously occurring spontaneous remyelination. Recent findings have unveiled the complex roles of innate and adaptive immune responses in remyelination and the immunoregulatory potential of the glial scar. Moreover, the intimate crosstalk between neuronal activity, oligodendrogenesis and myelination emphasizes the contribution of rehabilitation to functional recovery. With a view toward clinical applications, several therapeutic strategies have been devised to target SCI pathology, including genetic manipulation, administration of small therapeutic molecules, immunomodulation, manipulation of the glial scar and cell transplantation. The implementation of new tools such as cellular reprogramming for conversion of one somatic cell type to another or the use of nanotechnology and tissue engineering products provides additional opportunities for SCI repair. Given the complexity of the spinal cord tissue after injury, it is becoming apparent that combinatorial strategies are needed to rescue OLs and myelin at early stages after SCI and support remyelination, paving the way toward clinical translation.

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Myelin degeneration induced by mutant superoxide dismutase 1 accumulation promotes amyotrophic lateral sclerosis

Kim

Chung

et al. 2019

Glia

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Myelin is a specialized membrane that wraps around nerve fibers and is essential for normal axonal conduction in neurons. In the central nervous system, oligodendrocytes are responsible for myelin formation. Recent studies have reported pathological abnormalities in oligodendrocytes in human patients with amyotrophic lateral sclerosis (ALS) and a mouse model of ALS expressing the G93A mutation of the human superoxide dismutase 1 (mtSOD1). However, it is unclear whether oligodendrocyte pathology in ALS represents the primary dysfunction induced by mtSOD1 and how mtSOD1 contributes to oligodendrocyte degeneration and ALS pathogenesis. We analyzed GAL4‐VP16‐UAS transgenic zebrafish selectively expressing mtSOD1 in mature oligodendrocytes. We observed that mtSOD1 directly induced oligodendrocyte degeneration by disrupting the myelin sheath and downregulating monocarboxylate transporter 1 (MCT1), thereby causing spinal motor neuron degeneration. Pathological changes observed in this transgenic zebrafish were similar to the pathology observed in the SOD1G93A mouse model of ALS, which is characterized by expression of mtSOD1 in all cells. In addition, oligodendrocyte dysfunction induced by mtSOD1 was associated with anxiety‐related behavioral abnormalities, learning impairments, and motor defects in the early symptomatic stage. We also found that treatment with potassium channel inhibitors rescued behavioral abnormalities without rescuing MCT1 expression, suggesting that myelin disruption induces behavioral abnormalities independently of MCT1. These results indicate that mtSOD1‐induced dysfunction of mature oligodendrocytes is sufficient to induce motor neuron degeneration, thus informing future therapeutic strategies targeted at oligodendrocytes in ALS.

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Novel Potassium Channel Blocker, 4-AP-3-MeOH, Inhibits Fast Potassium Channels and Restores Axonal Conduction in Injured Guinea Pig Spinal Cord White Matter

Abstract: Novel potassium channel blocker, 4-AP-3-MeOH, inhibits fast potassium channels and restores axonal conduction in injured guinea pig spinal cord white matter.

Cited by 41 publications

References 51 publications

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

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

From demyelination to remyelination: The road toward therapies for spinal cord injury

Myelin degeneration induced by mutant superoxide dismutase 1 accumulation promotes amyotrophic lateral sclerosis

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