Trinh, O. T. P. | bioRxiv Science

bioRxiv2026

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.

neuroscience↗

bioRxiv2025

Behavioral profiling of hyperbaric oxygen as an intervention for chemotherapy-related functional impairments in male and female mice

Chemobrain or chemotherapy-related cognitive impairment (CRCI) affects up to 75% of cancer patients and survivors following chemotherapy treatments. Chemotherapy typically affects multiple domains including learning, memory, attention, executive function, and mood regulation, persisting for decades after treatment cessation and significantly diminishing cancer survivors quality of life. Despite its prevalence and long-term impact, effective interventions for CRCI remain limited. This study investigated the behavioral effects of HBO on mice exposed to chemotherapy drugs methotrexate (MTX) and 5-fluorouracil (5-FU). Adult male and female C57BL/6 mice received intraperitoneal injections of either saline or chemotherapy (Low-dose: MTX 37.5 mg/kg and 5-FU 50 mg/kg; High-dose: MTX 70 mg/kg and 5-FU 100 mg/kg) once a week for three weeks. Concurrently, subsets of mice underwent daily HBO (2.4 ATA, 90 minutes) five days a week for three weeks. Animals health was evaluated weekly, and behavioral assessment of cognitive, motor, and affective functions was conducted post-treatment. Our results showed that chemotherapy, especially at high-dose, impaired spatial memory and navigation, avoidance learning, fear discrimination, and anxiety regulation differently between males and females. HBO significantly alleviated chemotherapy-induced avoidance learning impairment in both sexes and improved coordinated running capacity in high-dose treated males. However, chemotherapy-HBO cotreatment increased spatial memory deficit in males and increased anxiety-like behaviors in females. In conclusion, even though HBO had some nuanced effects on the various domains, some reversal of CRCI effects were observed. Therefore, HBO should be further studied and considered as a potential treatment for chemobrain.

neuroscience↗