Inhibition of the RNA Regulator HuR Mitigates Spinal Cord Injury by Potently Suppressing Post-Injury Neuroinflammation

Neuroinflammation is a major driver of secondary tissue damage after spinal cord injury (SCI). Within minutes after SCI, activated microglia and astrocytes produce proinflammatory mediators such as TNF-α, IL-6, iNOS, and COX-2 which induce tissue injury through cytotoxicity, vascular hyperpermeability, and secondary ischemia. The inflammatory cascade is amplified by chemokines like CCL2 and CXCL1 which recruit immune cells to the injured site. HuR is an RNA regulator that promotes glial expression of many proinflammatory factors by binding to adenylate- and uridylate-rich elements in the 3' untranslated regions of their mRNAs. SRI-42127 is a small molecule which blocks HuR function by preventing its nucleocytoplasmic translocation. This study aimed to evaluate the potential of SRI-42127 to suppress neuroinflammation after SCI and improve functional outcome. Adult female mice underwent a T10 contusion injury and received SRI-42127 1 h post injury for up to 5 days. Locomotor function was assessed by open field testing, balance beam, and rotarod. Immunohistochemistry was used to assess lesion size, neuronal loss, myelin sparing, microglial/astroglial activation, and HuR localization. Inflammatory mediator expression was assessed by qPCR, immunohistochemistry, ELISA, or western blot. We found that SRI-42127 treatment significantly attenuated loss of locomotor function and post-SCI pain. There was a reduction in lesion size and neuronal loss with an increase in myelin sparing. Microglia and astrocytes showed reduced activation and reduced nucleocytoplasmic translocation of HuR. There was a striking suppression of proinflammatory mediators at the epicenter along with peripheral suppression of inflammatory responses in serum, liver, and spleen. In conclusion, HuR inhibition with SRI-42127 may be a viable therapeutic approach for suppressing neuroinflammatory responses after SCI and improving functional outcome.