Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.
4-Aminopyridine
/ pharmacology
Adult
Aged
Animals
Encephalomyelitis, Autoimmune, Experimental
/ pathology
Female
Humans
Male
Mice
Mice, Inbred C57BL
Middle Aged
Multiple Sclerosis
/ pathology
Neural Stem Cells
/ drug effects
Neuroprotective Agents
/ pharmacology
Optic Neuritis
/ pathology
Potassium Channel Blockers
/ pharmacology
Rats
Rats, Wistar
Retinal Degeneration
/ pathology
4-aminopyridine
NFAT
experimental optic neuritis
multiple sclerosis
optical coherence tomography
Journal
Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537
Informations de publication
Date de publication:
01 04 2020
01 04 2020
Historique:
received:
09
09
2019
revised:
08
12
2019
accepted:
20
01
2020
pubmed:
16
4
2020
medline:
1
8
2020
entrez:
16
4
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32293668
pii: 5820386
doi: 10.1093/brain/awaa062
doi:
Substances chimiques
Neuroprotective Agents
0
Potassium Channel Blockers
0
4-Aminopyridine
BH3B64OKL9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1127-1142Informations de copyright
© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.