Repurposing the cardiac glycoside digoxin to stimulate myelin regeneration in chemically‐induced and immune‐mediated mouse models of multiple sclerosis. Issue 10 (9th July 2022)

• Record Type: Journal Article
• Authors: Titus, Haley E.; Xu, Huan; Robinson, Andrew P.; Patel, Priyam A.; Chen, Yanan; Fantini, Damiano; Eaton, Valerie; Karl, Molly; Garrison, Eric D.; Rose, Indigo V. L.; Chiang, Ming Yi; Podojil, Joseph R.; Balabanov, Roumen; Liddelow, Shane A.; Miller, Robert H.; Popko, Brian; Miller, Stephen D.
• Is Part Of: Glia. Volume 70:Issue 10(2022)
• Page Start: 1950
• Page End: 1970
• Publication Date: 2022-07-09
• Subjects: digoxin -- immune tolerance -- multiple sclerosis -- myelin regeneration -- oligodendrocyte; Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.24231
• Languages: English
• ISSNs: 0894-1491

Abstract

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 MOG35‐55 ‐induced Th1/Th17‐mediated chronic EAE combined with tolerance induced by the i.v. infusion of biodegradable poly(lactide‐co‐glycolide) nanoparticles coupled with MOG35‐55 (PLG‐MOG35‐55 ) 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. Main Points: Digoxin promoted differentiation of oligodendrocyte lineage cells in vitro, promoted earlier/more robust recovery of myelin in vivo, and combined with immune tolerance ameliorated EAE disease symptoms and recovered the oligodendrocyte cell lineage.