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

Glia, 2022 · DOI: 10.1002/glia.24231 · Published: October 1, 2022

Immunology Neurology Regenerative Medicine & Stem Cells

Simple Explanation

Multiple sclerosis (MS) is a disease where the body's immune system attacks the protective covering of nerve fibers in the brain and spinal cord, called myelin. The ideal MS therapy would both specifically inhibit the underlying autoimmune response and promote repair/regeneration of myelin. Researchers investigated whether digoxin, a drug used for heart conditions, could help repair myelin. They found that digoxin can help cells that create myelin to mature, and can help with recovery after damage to myelin in mice. Combining digoxin with a treatment that suppresses the immune system response to myelin was found to improve outcomes in mice with an MS-like disease. These findings suggest that digoxin could be a useful treatment for MS, especially when combined with other therapies.

Study Duration

Not specified

Participants

Female naïve C57BL/6J (B6) mice

Evidence Level

Level 1, Animal Studies

Key Findings

1
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.
2
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.
3
Short-term digoxin monotherapy beginning at the peak of actively-induced C-EAE did not alter the course of clinical disease, nor significantly alter the number of brain and spinal cord OLs or Th1/17 inflammatory cytokine responses of splenocytes upon recall MOG35-55 stimulation.

Research Summary

This study demonstrates the capacity of digoxin to induce OPC differentiation in vitro, to robustly stimulate myelination in vivo in the chemically-induced cuprizone and lysophosphatidylcholine (LPC) demyelination/remyelination models, and in combination with PLG-Ag tolerance to ameliorate disease progression and promote recovery of OL lineage cell numbers in the immune-mediated MOG peptide-induced chronic experimental autoimmune encephalomyelitis (C-EAE) model. The results indicated more effective and sustained recovery of OL lineage cells and clinical symptoms in mice with C-EAE treated with the combination of MOG35-55-PLG tolerance and digoxin beginning at the peak of acute disease. Our results show that combining targeted myelin tolerance immunotherapy, thus avoiding the serious side effects of immunosuppressive therapies, with myelin repair/regenerative therapy is highly effective in ameliorating C-EAE, exceeding the effects of either therapy alone.

Practical Implications

Combination Therapy Potential

Combining digoxin with antigen-specific tolerance immunotherapy may offer a more effective treatment strategy for MS by addressing both the autoimmune response and myelin repair.

Clinical Trial Justification

The pre-clinical evidence supports initiating clinical trials to evaluate the safety and efficacy of digoxin, particularly in combination with immunomodulatory therapies, for MS patients.

Drug Repurposing Opportunity

Digoxin, being an FDA-approved drug, offers a potential for rapid translation into clinical use for myelin repair in MS, potentially reducing development timelines and costs.

Study Limitations

1
The study is limited to mouse models, and the results may not directly translate to human MS patients.
2
The study focuses on specific models of demyelination and EAE, which may not fully represent the heterogeneity of MS.
3
Further research is needed to fully elucidate the mechanisms by which digoxin promotes myelin regeneration and interacts with the immune system.

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