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


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
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

1127-1142

Informations 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.

Auteurs

Michael Dietrich (M)

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Valeria Koska (V)

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Christina Hecker (C)

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Peter Göttle (P)

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Alexander M Hilla (AM)

Department of Cell Physiology, Faculty of Biology and Biotechnology, Ruhr-University Bochum, Bochum, Germany.

Annemarie Heskamp (A)

Department of Cell Physiology, Faculty of Biology and Biotechnology, Ruhr-University Bochum, Bochum, Germany.

Klaudia Lepka (K)

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Andrea Issberner (A)

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Angelika Hallenberger (A)

Institute of Anatomy II, Medical Faculty, Heinrich Heine University Düsseldorf, Germany.

Christine Baksmeier (C)

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Julia Steckel (J)

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Lisanne Balk (L)

Department of Neurology, Amsterdam Neuroscience, MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.

Benjamin Knier (B)

Department of Experimental Neuroimmunology, Technische Universität München, Munich, Germany.

Thomas Korn (T)

Department of Experimental Neuroimmunology, Technische Universität München, Munich, Germany.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

Joachim Havla (J)

Institute of Clinical Neuroimmunology, Ludwig-Maximilians University, Munich, Germany.
Data Integration for Future Medicine consortium (DIFUTURE), Ludwig-Maximilians University, Munich, Germany.

Elena H Martínez-Lapiscina (EH)

Service of Neurology, Hospital Clinic, University of Barcelona, Spain Neuroimmunology Program, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Nuria Solà-Valls (N)

Service of Neurology, Hospital Clinic, University of Barcelona, Spain Neuroimmunology Program, Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Praveena Manogaran (P)

Neuroimmunology and Multiple Sclerosis Research, Department of Neurology, University Hospital Zürich and University of Zürich, Zurich, Switzerland.
Department of Information Technology and Electrical Engineering, Swiss Federal Institute of Technology, Zurich, Switzerland.

Elisabeth D Olbert (ED)

Neuroimmunology and Multiple Sclerosis Research, Department of Neurology, University Hospital Zürich and University of Zürich, Zurich, Switzerland.

Sven Schippling (S)

Neuroimmunology and Multiple Sclerosis Research, Department of Neurology, University Hospital Zürich and University of Zürich, Zurich, Switzerland.
Neuroscience Center Zurich, University of Zurich and Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.

Andrés Cruz-Herranz (A)

Division of Neuroinflammation and Glial Biology, Department of Neurology, University of California San Francisco, San Francisco, USA.

Hao Yiu (H)

Division of Neuroinflammation and Glial Biology, Department of Neurology, University of California San Francisco, San Francisco, USA.

Julia Button (J)

Division of Neuroimmunology and Neurological Infections, Johns Hopkins Hospital, Baltimore, USA.

Natalia Gonzalez Caldito (NG)

Division of Neuroimmunology and Neurological Infections, Johns Hopkins Hospital, Baltimore, USA.

Charlotte von Gall (C)

Institute of Anatomy II, Medical Faculty, Heinrich Heine University Düsseldorf, Germany.

Anne K Mausberg (AK)

Department of Neurology, University Hospital Essen, Essen, Germany.

Mark Stettner (M)

Department of Neurology, University Hospital Essen, Essen, Germany.

Hannah G Zimmermann (HG)

NeuroCure Clinical Research Center and Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health and Max Delbrueck Center for Molecular Medicine, Berlin, Germany.

Friedemann Paul (F)

NeuroCure Clinical Research Center and Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health and Max Delbrueck Center for Molecular Medicine, Berlin, Germany.

Alexander U Brandt (AU)

NeuroCure Clinical Research Center and Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health and Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
Department of Neurology, University of California, Irvine, USA.

Patrick Küry (P)

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Norbert Goebels (N)

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Orhan Aktas (O)

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Carsten Berndt (C)

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Shiv Saidha (S)

Division of Neuroimmunology and Neurological Infections, Johns Hopkins Hospital, Baltimore, USA.

Ari J Green (AJ)

Division of Neuroinflammation and Glial Biology, Department of Neurology, University of California San Francisco, San Francisco, USA.
Department of Ophthalmology, University of California San Francisco, San Francisco, USA.

Peter A Calabresi (PA)

Division of Neuroimmunology and Neurological Infections, Johns Hopkins Hospital, Baltimore, USA.

Dietmar Fischer (D)

Department of Cell Physiology, Faculty of Biology and Biotechnology, Ruhr-University Bochum, Bochum, Germany.

Hans-Peter Hartung (HP)

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

Philipp Albrecht (P)

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.

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Classifications MeSH