Inhibiting microglia proliferation after spinal cord injury improves recovery in mice and nonhuman primates

Theranostics. 2021 Jul 31;11(18):8640-8659. doi: 10.7150/thno.61833. eCollection 2021.

Abstract

No curative treatment is available for any deficits induced by spinal cord injury (SCI). Following injury, microglia undergo highly diverse activation processes, including proliferation, and play a critical role on functional recovery. In a translational objective, we investigated whether a transient pharmacological reduction of microglia proliferation after injury is beneficial for functional recovery after SCI in mice and nonhuman primates. Methods: The colony stimulating factor-1 receptor (CSF1R) regulates proliferation, differentiation, and survival of microglia. We orally administrated GW2580, a CSF1R inhibitor that inhibits microglia proliferation. In mice and nonhuman primates, we then analyzed treatment outcomes on locomotor function and spinal cord pathology. Finally, we used cell-specific transcriptomic analysis to uncover GW2580-induced molecular changes in microglia. Results: First, transient post-injury GW2580 administration in mice improves motor function recovery, promotes tissue preservation and/or reorganization (identified by coherent anti-stokes Raman scattering microscopy), and modulates glial reactivity. Second, post-injury GW2580-treatment in nonhuman primates reduces microglia proliferation, improves motor function recovery, and promotes tissue protection. Finally, GW2580-treatment in mice induced down-regulation of proliferation-associated transcripts and inflammatory associated genes in microglia that may account for reduced neuroinflammation and improved functional recovery following SCI. Conclusion: Thus, a transient oral GW2580 treatment post-injury may provide a promising therapeutic strategy for SCI patients and may also be extended to other central nervous system disorders displaying microglia activation.

Keywords: microglia; primates; proliferation; rodent; spinal cord injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anisoles / pharmacology
  • Cell Proliferation / drug effects
  • Cheirogaleidae
  • Disease Models, Animal
  • Gene Expression / genetics
  • Inflammation / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / drug effects
  • Microglia / metabolism*
  • Neurogenesis
  • Neuroinflammatory Diseases
  • Pyrimidines / pharmacology
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / drug effects
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Recovery of Function / drug effects
  • Spinal Cord Injuries / physiopathology*
  • Transcriptome / genetics

Substances

  • 5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine
  • Anisoles
  • Csf1r protein, mouse
  • Pyrimidines
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor