High Doses of 4-Aminopyridine Improve Functionality in Chronic Complete Spinal Cord Injury Patients with MRI Evidence of Cord Continuity

Grijalva, Israel; García‐Pérez, Angélica; Diaz, J. M.; Aguilar, Sergio io Hernández; Mino, D; Santiago-Rodríguez, Efraín; Guı́zar-Sahagún, Gabriel; Castañeda‐Hernández, Gilberto; Maldonado-Julián, Héctor; Madrazo, Ignacio

doi:10.1016/j.arcmed.2010.10.001

Cited by 24 publications

(29 citation statements)

References 33 publications

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“…In this aspect, Grijalva et al (2010) showed that high dose of 4-AP treatment resulted in significant functional recovery in patients of chronic spinal cord injury with cord continuity at injury site. Although high doses of 4-AP lead to troubling side-effects (Hayes, 2004), we show that its derivative 4-AP-3-Me mimics the effects of 4-AP at lower doses, suggesting an alternative treatment to 4-AP.…”

Section: Discussionmentioning

confidence: 99%

Restoration of Visual Function by Enhancing Conduction in Regenerated Axons

Bei

Lee

et al. 2016

Cell

219

161

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Although a number of repair strategies have been shown to promote axon outgrowth following neuronal injury in the mammalian central nervous system, it remains unclear whether regenerated axons establish functional synapses and support behavior. Here, in both juvenile and adult mice, we show that either PTEN and SOCS3 co-deletion, or co-overexpression of osteopontin (OPN)/insulin-like growth factor 1 (IGF1)/ciliary neurotrophic factor (CNTF), induces regrowth of retinal axons and formation of functional synapses in the superior colliculus (SC), but not significant recovery of visual function. Further analyses suggest that regenerated axons fail to conduct action potentials from the eye to the SC due to lack of myelination. Consistent with this idea, administration of voltage-gated potassium channel blockers restores conduction and results in increased visual acuity. Thus, enhancing both regeneration and conduction effectively improves function after optic nerve injury.

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Section: Discussionmentioning

confidence: 99%

Restoration of Visual Function by Enhancing Conduction in Regenerated Axons

Bei

Lee

et al. 2016

Cell

219

161

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“…Despite being studied for over 30 years in settings of chronic neurological illness, there are no prior indications that 4‐AP would provide durable improvements that are essential for regenerative applications (e.g. Lundh et al , , ; Jones et al , ; Stefoski et al , ; Hayes et al , ; Polman et al , ; Segal & Brunnemann, ; Wolfe et al , ; DeForge et al , ; Grijalva et al , ; Claassen et al , ; Kremmyda et al , ; Jensen et al , ; Strupp et al , ). Moreover, the only two published examinations of 4‐AP in acute settings provide no evidence for utility in experimental SCI (Haghighi et al , ) or in acute vestibular failure (Beck et al , ).…”

Section: Discussionmentioning

confidence: 99%

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

Tseng

Clark

et al. 2016

EMBO Mol Med

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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.

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“…Aminopyridine is a potassium channel blocker that improves nerve conduction in demyelinated axons (54,57), with both motor and sensory functional improvement (60,55). However, more studies are necessary to prove that aminopyridine produces better results than a placebo (55).…”

Section: Therapeutic Possibilitiesmentioning

confidence: 99%

Therapeutic approaches for spinal cord injury

Cristante¹,

Filho²,

Marcon³

et al. 2012

Clinics

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This study reviews the literature concerning possible therapeutic approaches for spinal cord injury. Spinal cord injury is a disabling and irreversible condition that has high economic and social costs. There are both primary and secondary mechanisms of damage to the spinal cord. The primary lesion is the mechanical injury itself. The secondary lesion results from one or more biochemical and cellular processes that are triggered by the primary lesion. The frustration of health professionals in treating a severe spinal cord injury was described in 1700 BC in an Egyptian surgical papyrus that was translated by Edwin Smith; the papyrus reported spinal fractures as a “disease that should not be treated.” Over the last two decades, several studies have been performed to obtain more effective treatments for spinal cord injury. Most of these studies approach a patient with acute spinal cord injury in one of four manners: corrective surgery or a physical, biological or pharmacological treatment method. Science is unraveling the mechanisms of cell protection and neuroregeneration, but clinically, we only provide supportive care for patients with spinal cord injuries. By combining these treatments, researchers attempt to enhance the functional recovery of patients with spinal cord injuries. Advances in the last decade have allowed us to encourage the development of experimental studies in the field of spinal cord regeneration. The combination of several therapeutic strategies should, at minimum, allow for partial functional recoveries for these patients, which could improve their quality of life.

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High Doses of 4-Aminopyridine Improve Functionality in Chronic Complete Spinal Cord Injury Patients with MRI Evidence of Cord Continuity

Cited by 24 publications

References 33 publications

Restoration of Visual Function by Enhancing Conduction in Regenerated Axons

Restoration of Visual Function by Enhancing Conduction in Regenerated Axons

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

Therapeutic approaches for spinal cord injury

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