4‐Aminopyridine improves clinical signs in multiple sclerosis

Stefoski, Dusan; Davis, Floyd A.; Faut, M.; Schauf, C. L.

doi:10.1002/ana.410210113

Cited by 148 publications

(67 citation statements)

References 31 publications

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“…4-aminopyridine (4-AP), a potassium channel blocker, has been used to temporarily relieve the neurological symptoms in MS patients at a dose 1000 times lower than that required to restore electrical transmission in demyelinated fibers. 60 Evidence has shown that low-dose 4-AP treatment enhances synaptic transmission by increasing synaptic vesicle release. 61 On the other hand, both dendritic beading and the loss of syn- The marked reduction in synaptophysin and synapsin I immunoreactivity was well correlated with EAE severity.…”

Section: Discussionmentioning

confidence: 99%

Dendritic and Synaptic Pathology in Experimental Autoimmune Encephalomyelitis

Zhu

Luo

Moore

et al. 2003

The American Journal of Pathology

110

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Evidence has shown that excitotoxicity may contribute to the loss of central nervous system axons and oligodendrocytes in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Because dendrites and synapses are vulnerable to excitotoxicity, we examined these structures in acute and chronic models of EAE. Immunostaining for microtubule-associated protein-2 showed that extensive dendritic beading occurred in the white matter of the lumbosacral spinal cord (LSSC) during acute EAE episodes and EAE relapses. Retrograde labeling confirmed that most motoneuron dendrites were beaded in the white matter of the LSSC in acute EAE. In contrast, only mild swelling was observed in the gray matter of the LSSC. Dendritic beading showed marked recovery during EAE remission and after EAE recovery. In addition, synaptophysin, synapsin I, and PSD-95 immunoreactivities were significantly reduced in both the gray and white matter of the LSSC during acute EAE episodes and EAE relapses, but showed partial recovery during EAE remission and after EAE recovery. Pathologically, both dendritic beading and the reduction in synaptic protein immunoreactivity were well correlated with inflammatory cell infiltration in the LSSC at different EAE stages. We propose that dendritic and synaptic damage in the spinal cord may contribute to the neurological deficits in EAE. Central nervous system (CNS) inflammation and neurodegeneration are two major pathological processes in multiple sclerosis (MS). Understanding the pathology and mechanisms of CNS degeneration in MS is essential for protecting neural structures and functions in MS patients. In addition to the demyelination and the loss of oligodendrocytes, axonal degeneration in MS has received substantial attention. It has been realized that axonal loss starts early in the disease course, 1,2 and that the accumulation of axonal damage parallels in general the progressive neurological dysfunction in MS patients.3

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Section: Discussionmentioning

confidence: 99%

Dendritic and Synaptic Pathology in Experimental Autoimmune Encephalomyelitis

Zhu

Luo

Moore

et al. 2003

The American Journal of Pathology

110

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“…One subject demonstrated a clear gait improvement that was proven to be reversible. The quality of the gait improvement was not described [Stefoski et al 1987].…”

Section: Immediate-release 4-aminopyridinementioning

confidence: 99%

4-Aminopyridine for symptomatic treatment of multiple sclerosis: a systematic review

Jensen

Ravnborg

Dalgas

2013

Ther Adv Neurol Disord

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This systematic review summarizes the existing evidence on the effect of 4-aminopyridine (4-AP) as a symptomatic treatment of decreased walking capacity in patients with multiple sclerosis (MS) when administered as an immediate release compound and a slow release compound. It summarizes existing evidence on the basic mechanisms of 4-AP from experimental studies and evidence on the clinical use of the compound. A systematic literature search was conducted of the following databases: PubMed and EMBASE. Thirty-five studies were included in the review divided into 16 experimental studies, two clinical studies with paraclinical endpoints and 17 clinical studies with clinical endpoints. Animal studies show that 4-AP can improve impulse conduction through demyelinated lesions. In patients with MS this translates into improved walking speed and muscle strength of the lower extremities in a subset of patients at a level that is often of clinical relevance. Phase III trials demonstrate approximately 25% increase in walking speed in roughly 40% and improved muscle strength in the lower extremities. Furthermore, 4-AP might have an effect on other domains such as cognition, upper extremity function and bowel and bladder, but this warrants further investigation. Side effects are mainly mild to moderate, consisting primarily of paraesthesia, dizziness, nausea/vomiting, falls/balance disorders, insomnia, urinary tract infections and asthenia. Side effects are worse when administered intravenously and when administered as an immediate release compound. Serious adverse events are rarely seen in the marketed clinical dosages. In conclusion, 4-AP is easy and safe to use. Slow release 4-AP shows more robust clinical effects and a more beneficial side-effect profile than immediate release 4-AP.

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“…Similar to neurotrauma, multiple sclerosis has a long history of clinical testing of 4-AP [50][51][52][53][54][55][56][57][58][59][60][61] . Recently, a series of carefully designed clinical trials have provided significant improvement in walking ability of multiple sclerosis patients [43,[62][63][64] .…”

Section: The Effects Of 4-ap In Human Testingmentioning

confidence: 99%

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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4‐Aminopyridine improves clinical signs in multiple sclerosis

Cited by 148 publications

References 31 publications

Dendritic and Synaptic Pathology in Experimental Autoimmune Encephalomyelitis

Dendritic and Synaptic Pathology in Experimental Autoimmune Encephalomyelitis

4-Aminopyridine for symptomatic treatment of multiple sclerosis: a systematic review

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

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