Abstract
Spinal cord injury (SCI) induces a pronounced neuroinflammation driven by activation and proliferation of resident microglia as well as infiltrating peripheral monocyte-derived macrophages. Depending on the time post-lesion, positive and detrimental influences of microglia/macrophages on axonal regeneration had been reported after SCI, raising the issue whether their modulation may represent an attractive therapeutic strategy. Colony-stimulating factor 1 (CSF1) regulates microglia/macrophages proliferation, differentiation and survival thus, pharmacological treatments using CSF1 receptor (CSF1R) inhibitors had been used to ablate microglia. We analyzed the effect of chronic (10 weeks) food diet containing GW2580 (a CSF1R inhibitor) in mice that underwent lateral spinal cord hemisection (HS) at vertebral thoracic level 9. Treatment started 4 weeks prior to SCI and continued until 6 weeks post-lesion. We first demonstrate that GW2580 treatment did not modify microglial response in non-injured spinal cords. Conversely, a strong decrease in proliferating microglia was observed following SCI. Second, we showed that GW2580 treatment improved some parameters of motor recovery in injured animals through better paw placement. Using in and ex vivo magnetic resonance imaging (MRI), we then established that GW2580 treatment had no effect on lesion extension and volume. However, histological analyses revealed that GW2580-treated animals had reduced gliosis and microcavity formation following SCI. In conclusion, CSF1R blockade using GW2580 specifically inhibits SCI-induced microglia/macrophages proliferation, reduces gliosis and microcavity formations and improves fine motor recovery after incomplete SCI. Preventing microglial proliferation may offer therapeutic approach to limit neuroinflammation, promote tissue preservation and motor recovery following SCI.
Highlights
Spinal cord injuries (SCIs) affect between 2.5 million and 4 million patients worldwide (van den Berg et al, 2010)
In non-injured mice, immunohistochemistry using anti-BrdU showed no effect of GW2580 treatment, no difference in the density of total microglia, proliferating cells (BrdU+ cells) and proliferating microglia was observed between treated and untreated animals (Figures 1A,H,O and Supplementary Figures S1A–I, dashed lines)
CSF1 receptor (CSF1R) blockade resulted in reduced gliosis and better tissue preservation, suggesting a positive role of GW2580-treatment on Spinal cord injury (SCI) pathophysiology
Summary
Spinal cord injuries (SCIs) affect between 2.5 million and 4 million patients worldwide (van den Berg et al, 2010). Other studies report an anti-inflammatory role of monocytes derived macrophages that is mediated by interleukin 10 overexpression, after SCI (Popovich et al, 1999; Shechter et al, 2009). These studies highlight both favorable and detrimental influences of microglia/macrophages in CNS pathophysiology. GW2580 is an orally available selective inhibitor of the tyrosine kinase activity of CSF1R and, to a lesser extent, other related kinases such as FMS tyrosine kinase 3 (FLT3, CD135) and oncogene KIT (c-Kit, CD117) This molecule selectively inhibits microglia/monocytes proliferation (Conway et al, 2005). Inhibiting microglia proliferation may provide a viable therapeutic approach to reduce neuroinflammation, promote tissue preservation, and motor recovery after SCI
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
