Introduction: Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality with a bimodal age peak in childhood and age>65. TNF has a complex modulatory role in both the acute and chronic phases of TBI. The soluble form of tumor necrosis factor (TNF) preferentially binds its receptor TNFR1, promoting inflammation. XPro1595, specifically binds to and neutralizes soluble TNF, effectively inhibiting TNFR1 and subsequent inflammation, including GFAP-positive astrocyte reactivity. We hypothesize that in a pediatric mouse model of TBI, administration of XPro1595 will reduce GFAP expression after TBI.
Methods: C57Bl/6 pediatric mice were anesthetized and then underwent craniotomy, then either underwent controlled cortical impact to simulate TBI or a sham procedure. Each group was divided again to receive either vehicle or XPro1595. Mice were then sacrificed at 3- or 30-days post injury, brain tissue was collected and prepared for immunohistochemical and western blot analysis.
Results: 3-day post-TBI mice demonstrated expected elevations of GFAP compared to sham animals. On IHC, TBI+Xpro animals had a statistically significant decrease in GFAP expression compared to TBI+veh. On WB, TBI+veh again had elevated increase in GFAP while the mild elevation for TBI+XPro animals had lost significance. 30-day post-TBI mice demonstrated less significant changes on IHC except in the area of cortical injury which was still elevated compared to Sham+xpro. On WB, TBI+Xpro was now significantly decreased in expression.
Conclusion : In the short term, TBI produced an expected elevation in GFAP in the injured animal. At 30 days, the levels of GFAP had returned to a closer to normal level. Administration of Xpro caused reductions in GFAP expression in the sham and TBI groups at both short- and long-term intervals. Further study with additional biomarkers, as well as behavioral testing at similar timepoints, will help to elucidate the impact of TNFR1 inhibition in pediatric TBI
.jpg)
