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Pharmacologic Inhibition of Toll-like Receptor-4 (TLR4) Attenuates Traumatic Brain Injury (TBI)-Induced Neuroinflammation , Improving Cognitive Outcomes.
Young H. Chun, MD1; Jose Alonso-Escalante, MD2; Bruno Soares, MD1; William Fulton, BS1; Chhinder Sodhi, PhD1; David Hackam, MD, PhD1; Isam W. Nasr, MD1
1Johns Hopkins University, Baltimore, MD; 2Allegheny General Hospital, Pittsburgh, PA

Background: TBI induces a robust neuroinflammatory response that activates the innate immune system. We sought to investigate the effect of pharmacologically inhibiting the innate immune signaling pathways using a novel TLR4 inhibitor, C34 in a murine TBI model.

Methods: A controlled cortical impact murine TBI model using three groups: (1)wild-type (WT) control, (2)WT+C34 (1-day treatment), (3)WT+C34 (7-day treatment). MRI measured lesion volume. PCR measured cytokine gene expression. Behavioral testing was initiated on post-injury day (PID)7 and 28. Statistical analysis: Student's T-test and One-way ANOVA.

Results: Brain injury volumes in WT (2.11.687mm3, n=11) and WT+C34 mice (3.22mm3, n=7) were not significantly different on PID7. The WT+C34 group had significantly decreased pro-inflammatory cytokines (TNFα, p=0.0010, IL-1, p=0.03) and anti-inflammatory cytokines (IL-10 p=0.0067, TGFβp=0.004) compared to WTs on PID 1. Apoptosis markers, Caspase (p=0.0001), Bad (p=0.0001) and Bax (p=0.02) were significantly downregulated in the treatment group on PID1; as were necroptosis markers MLKL (p=0.02), RIPK1 (p=0.0001), and RIPK3 (p=0.0001). There was no difference in gene expression on PID7 or PID35. Behavioral testing (water-maze) showed that 7-day C34 treatment significantly worsened outcome (p=0.04) compared to the sham group, whereas the 1-day treatment group did not have a significant difference in outcome compared to the sham group.

Conclusions: Our findings demonstrate that TLR4 plays a role in the early pathogenesis of the neuroinflammatory response to TBI. Early, short-term pharmacologic inhibition of the TLR4 pathway with C34 attenuates the inflammatory response and leads to improved neurocognitive outcomes compared to the prolonged 7-day treatment.

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