Abstract
Microglia are major players in scar formation after an injury to the spinal cord. Microglia proliferation, differentiation, and survival are regulated by the colony-stimulating factor 1 (CSF1). Complete microglia elimination using CSF1 receptor (CSF1R) inhibitors worsens motor function recovery after spinal injury (SCI). Conversely, a 1-week oral treatment with GW2580, a CSF1R inhibitor that only inhibits microglia proliferation, promotes motor recovery. Here, we investigate whether prolonged GW2580 treatment further increases beneficial effects on locomotion after SCI. We thus assessed the effect of a 6-week GW2580 oral treatment after lateral hemisection of the spinal cord on functional recovery and its outcome on tissue and cellular responses in adult mice. Long-term depletion of microglia proliferation after SCI failed to improve motor recovery and had no effect on tissue reorganization, as revealed by ex vivo diffusion-weighted magnetic resonance imaging. Six weeks after SCI, GW2580 treatment decreased microglial reactivity and increased astrocytic reactivity. We thus demonstrate that increasing the duration of GW2580 treatment is not beneficial for motor recovery after SCI.
Highlights
Traumatic spinal cord injury (SCI) has a worldwide incidence of 10.5 cases per 100,000, with 600,000 to 900,000 additional cases annually [1]
To investigate whether prolonged inhibition of microglia proliferation further improves motor outcomes, we studied the effect of longterm (6 weeks) GW2580 treatment starting immediately after SCI (Figure 1A)
We show that prolonged GW2580 treatment starting immediately after SCI
Summary
Traumatic spinal cord injury (SCI) has a worldwide incidence of 10.5 cases per 100,000, with 600,000 to 900,000 additional cases annually [1]. Mice with a thoracic (T10/T11) spinal cord contusion that were continuously treated with PLX5622 between 3 weeks prior to SCI to 5 weeks post-injury displayed worsening motor recovery [6]. Eradication of microglia using an oral PLX3397-treatment in mice between 7 days before SCI to 4 weeks after severe T10 spinal cord crush led to impaired locomotor function and exacerbated tissue damage [8]. A GW2580 treatment beginning 4 weeks before the lesion and continuing for 6 weeks after SCI was associated with an improvement in fine motor recovery and a decrease in gliosis after a T9 spinal cord hemisection [10]. One-week (in mice) and two-week (in nonhuman primates) post-injury GW2580 treatment improved functional motor recovery and was associated with a modulation of tissue damage. We demonstrate that prolonged GW2580 treatment is not beneficial after SCI
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