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4-Aminopyridine promotes functional recovery and remyelination in acute peripheral nerve injury.

ABSTRACT: Traumatic peripheral nerve damage is a major medical problem without effective treatment options. In repurposing studies on 4-aminopyridine (4-AP), a potassium channel blocker that provides symptomatic relief in some chronic neurological afflictions, we discovered this agent offers significant promise as a small molecule regenerative agent for acute traumatic nerve injury. We found, in a mouse model of sciatic crush injury, that sustained early 4-AP administration increased the speed and extent of behavioral recovery too rapidly to be explained by axonal regeneration. Further studies demonstrated that 4-AP also enhanced recovery of nerve conduction velocity, promoted remyelination, and increased axonal area post-injury. We additionally found that 4-AP treatment enables distinction between incomplete and complete lesions more rapidly than existing approaches, thereby potentially addressing the critical challenge of more effectively distinguishing injured individuals who may require mutually exclusive treatment approaches. Thus, 4-AP singularly provides both a new potential therapy to promote durable recovery and remyelination in acute peripheral nerve injury and a means of identifying lesions in which this therapy would be most likely to be of value.

SUBMITTER: Tseng KC

PROVIDER: S-EPMC5167128 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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4-Aminopyridine promotes functional recovery and remyelination in acute peripheral nerve injury.

Tseng Kuang-Ching KC Li Haiyan H Clark Andrew A Sundem Leigh L Zuscik Michael M Noble Mark M Elfar John J

EMBO molecular medicine 20161201 12

Traumatic peripheral nerve damage is a major medical problem without effective treatment options. In repurposing studies on 4-aminopyridine (4-AP), a potassium channel blocker that provides symptomatic relief in some chronic neurological afflictions, we discovered this agent offers significant promise as a small molecule regenerative agent for acute traumatic nerve injury. We found, in a mouse model of sciatic crush injury, that sustained early 4-AP administration increased the speed and extent ...[more]

PMID: 27861125

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Project description:IntroductionPeripheral nerve injury (PNI) often leads to significant functional loss in patients and poses a challenge to physicians since treatment options for improving functional outcomes are limited. Recent studies suggest that erythropoietin and glucocoticoids have beneficial effects as mediators of neuro-regenerative processes. We hypothesized that combination treatment with erythropoietin and glucocoticoids would have a synergistic effect on functional outcome after PNI.Materials and methodsSciatic nerve crush injury was simulated in ten-week-old male C57BL/6 mice. The mice were divided into four groups according to the type of drugs administered (control, erythropoietin, dexamethasone, and erythropoietin with dexamethasone). Motor functional recovery was monitored by walking track analysis at serial time points up to 28 days after injury. Morphological analysis of the nerve was performed by immunofluorescent staining for neurofilament (NF) heavy chain and myelin protein zero (P0) in cross-sectional and whole-mount nerve preparations. Additionally, morphological analysis of the muscle was performed by Hematoxylin and eosin staining.ResultsCombination treatment with erythropoietin and dexamethasone significantly improved the sciatic functional index at 3, 7, 14, and 28 days after injury. Fluorescence microscopy of cross sectional nerve revealed that the combination treatment increased the ratio of P0/NF-expressing axons. Furthermore, confocal microscopy of the whole-mount nerve revealed that the combination treatment increased the fluorescence intensity of P0 expression. The cross-sectional area and minimum Feret's diameter of the muscle fibers were significantly larger in the mice which received combination treatment than those in the controls.ConclusionOur results demonstrated that combination treatment with erythropoietin and dexamethasone accelerates functional recovery and reduces neurogenic muscle atrophy caused by PNI in mice, which may be attributed to the preservation of myelin and Schwann cell re-myelination. These findings may provide practical therapeutic options for patients with acute PNI.

Dataset Information

4-Aminopyridine promotes functional recovery and remyelination in acute peripheral nerve injury.

Publications

4-Aminopyridine promotes functional recovery and remyelination in acute peripheral nerve injury.

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