Inhibiting microglia proliferation after spinal cord injury improves recovery in mice and nonhuman primates.
Theranostics
; 11(18): 8640-8659, 2021.
Article
em En
| MEDLINE
| ID: mdl-34522204
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Traumatismos da Medula Espinal
/
Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos
/
Microglia
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article