Targeting the RNA regulator HuR in acute traumatic brain injury mitigates secondary injury and improves functional outcome by suppressing neuroinflammation

Traumatic brain injury (TBI) affects ~2.5 million people annually in the US. Minutes after TBI, microglia and astrocytes initiate a neuroinflammatory cascade which promotes secondary injury via cytotoxicity, blood-brain barrier damage, edema, and immune cell recruitment. HuR, an RNA regulator, plays a critical role in the glial response by promoting the expression of proinflammatory mediators including IL-6, IL-1{beta}, TNF-, COX-2, CCL2, and CXCL1 via adenine and uridine-rich elements in the 3' untranslated region of their mRNAs. Here, we assessed SRI-42127, a small molecule HuR inhibitor developed by our group, on neuroinflammatory responses, secondary injury, and functional outcome after TBI. Male mice underwent controlled cortical impact (CCI) followed by peripheral administration of SRI-42127. Functional outcomes assessed included: motor function (balance beam/rotarod) and memory function (object location/recognition). Edema, lesion volume, and BBB permeability were assessed by MRI, brain water content, and Evans blue dye extravasation. HuR nucleocytoplasmic translocation, neuronal loss/apoptosis, microglial and astrocyte activation, and neutrophil infiltration were quantified by immunohistochemistry. Proinflammatory mediator induction was assessed by RT-qPCR and/or immunoblot. Results showed that SRI-42127 treatment improved spatial memory and fine motor performance in the first week in parallel with a reduction in edema, vascular permeability, lesion size, and neuronal loss/apoptosis. There was attenuated microglial activation and astrogliosis, decreased neutrophil infiltration, and suppression of proinflammatory mediator induction. Mechanistically, SRI-42127 inhibited HuR nucleocytoplasmic translocation in microglia and astrocytes. In summary, SRI-42127 potently suppresses neuroinflammation and secondary injury after TBI, improves functional outcomes, and identifies HuR as a new therapeutic target in TBI.