Pifithrin-μ modulates microglial activation and promotes histological recovery following spinal cord injury.

Abstract

Treatments immediately after spinal cord injury (SCI) are anticipated to decrease neuronal death, disruption of neuronal connections, demyelination, and inflammation, and to improve repair and functional recovery. Currently, little can be done to modify the acute phase, which extends to the first 48hours post-injury. Efforts to intervene have focused on the subsequent phases - secondary (days to weeks) and chronic (months to years) - to both promote healing, prevent further damage, and support patients suffering from SCI. We used a contusion model of SCI in female mice, and delivered a small molecule reagent during the early phase of injury. Histological and behavioral outcomes were assessed and compared. We find that the reagent Pifithrin-μ (PFT-μ) acts early and directly on microglia in vitro, attenuating their activation. When administered during the acute phase of SCI, PFT-μ resulted in reduced lesion size during the initial inflammatory phase, and reduced the numbers of pro-inflammatory microglia and macrophages. Treatment with PFT-μ during the early stage of injury maintained a stable anti-inflammatory environment. Our results indicate that a small molecule reagent PFT-μ has sustained immunomodulatory effects following a single dose after injury.