Title

Repurposing the cardiac glycoside digoxin to stimulate myelin regeneration in chemically-induced and immune-mediated mouse models of multiple sclerosis

Authors

Haley E. Titus, Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Huan Xu, Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Andrew P. Robinson, Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Priyam A. Patel, Quantitative Data Science Core Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Yanan Chen, Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Damiano Fantini, Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Valerie Eaton, Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Molly Karl, Department of Anatomy and Cell Biology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.
Eric D. Garrison, Department of Anatomy and Cell Biology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.
Indigo V. Rose, Neuroscience Institute and Departments of Neuroscience, & Physiology, and Ophthalmology, New York University Grossman School of Medicine, New York, New York, USA.
Ming Yi Chiang, Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Joseph R. Podojil, Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Roumen Balabanov, Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Shane A. Liddelow, Neuroscience Institute and Departments of Neuroscience, & Physiology, and Ophthalmology, New York University Grossman School of Medicine, New York, New York, USA.
Robert H. Miller, Department of Anatomy and Cell Biology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.
Brian Popko, Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Stephen D. Miller, Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Document Type

Journal Article

Publication Date

7-9-2022

Journal

Glia

DOI

10.1002/glia.24231

Keywords

digoxin; immune tolerance; multiple sclerosis; myelin regeneration; oligodendrocyte

Abstract

Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by inflammation, demyelination, and neurodegeneration. The ideal MS therapy would both specifically inhibit the underlying autoimmune response and promote repair/regeneration of myelin as well as maintenance of axonal integrity. Currently approved MS therapies consist of non-specific immunosuppressive molecules/antibodies which block activation or CNS homing of autoreactive T cells, but there are no approved therapies for stimulation of remyelination nor maintenance of axonal integrity. In an effort to repurpose an FDA-approved medication for myelin repair, we chose to examine the effectiveness of digoxin, a cardiac glycoside (Na /K ATPase inhibitor), originally identified as pro-myelinating in an in vitro screen. We found that digoxin regulated multiple genes in oligodendrocyte progenitor cells (OPCs) essential for oligodendrocyte (OL) differentiation in vitro, promoted OL differentiation both in vitro and in vivo in female naïve C57BL/6J (B6) mice, and stimulated recovery of myelinated axons in B6 mice following demyelination in the corpus callosum induced by cuprizone and spinal cord demyelination induced by lysophosphatidylcholine (LPC), respectively. More relevant to treatment of MS, we show that digoxin treatment of mice with established MOG -induced Th1/Th17-mediated chronic EAE combined with tolerance induced by the i.v. infusion of biodegradable poly(lactide-co-glycolide) nanoparticles coupled with MOG (PLG-MOG ) completely ameliorated clinical disease symptoms and stimulated recovery of OL lineage cell numbers. These findings provide critical pre-clinical evidence supporting future clinical trials of myelin-specific tolerance with myelin repair/regeneration drugs, such as digoxin, in MS patients.

Department

Anatomy and Regenerative Biology

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