Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis

Abstract

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.

4-Aminopyridine is not just a symptomatic therapy, it has a neuroprotective effect – Commentary

“…In line with the experimental data, during concurrent 4AP therapy, degeneration of the macular retinal nerve fiber layer was reduced over 2 years. 12 However, these findings need to be corroborated in independent and ideally prospective cohort studies, especially since the effect size was low and the rates of peripapillary retinal nerve fiber layer and ganglion cell/inner plexiform layer thinning did not differ significantly between the groups.…”

4-aminopyridine is not just a symptomatic therapy, it has a neuroprotective effect – Yes

“…Very recently, Dietrich et al 8 confirmed these findings in a large multi-center effort that studied the neuroprotective effects of 4-AP in a myelin oligodendrocyte glycoprotein (MOG)-induced EAE–optic neuritis (ON) model, an optic nerve crush model and retrospectively in MS patients. In line with the other EAE studies, treatment with 4-AP gave better clinical scores in mice with EAE-ON compared to sham-treated mice.…”

“…In addition, also in this work, 4-AP did not inhibit the proliferative response of antigenspecific T-cells but the treated mice had less severe demyelination and less cellular infiltrates than control mice. 7 Very recently, Dietrich et al 8 confirmed these findings in a large multi-center effort that studied the neuroprotective effects of 4-AP in a myelin oligodendrocyte glycoprotein (MOG)-induced EAE-optic neuritis (ON) model, an optic nerve crush model and retrospectively in MS patients. In line with the other EAE studies, treatment with 4-AP gave better clinical scores in mice with EAE-ON compared to sham-treated mice.…”

Inflammation in the anterior visual pathway in multiple sclerosis: what do the animal models teach us?

“…Since EAE is the most commonly used animal model for MS with a predominant inflammatory component, it is regularly used to test the effects of new anti-inflammatory treatment strategies and to better understand the pathophysiological mechanisms of on-and off-label drugs. Recent structural and functional measurements such as OCT, VEP, optomotor response, optokinetic response, and electroretinogram (ERG), thereby allow a sensitive longitudinal evaluation of structure and function [79,82,96,106,113,114,[122][123][124][125][126] . Advantages and disadvantages of these in vivo readouts, which are increasingly being used in animal models, are described in Table 2.…”