Background: Traumatic brain injury (TBI) begins with the application of mechanical force to the head or brain, which initiates systemic and cellular processes that are hallmarks of the disease. The pathological cascade of secondary injury processes, including inflammation, can exacerbate brain injury-induced morbidities and thus represents a plausible target for pharmaceutical therapies. We have pioneered research on post-traumatic sleep, identifying that injury-induced sleep lasting for 6 h in brain-injured mice coincides with increased cortical levels of inflammatory cytokines, including tumor necrosis factor (TNF). Here, we apply post-traumatic sleep as a physiological bio-indicator of inflammation. We hypothesized the efficacy of novel TNF receptor (TNF-R) inhibitors could be screened using post-traumatic sleep and that these novel compounds would improve functional recovery following diffuse TBI in the mouse.
Methods: Three inhibitors of TNF-R activation were synthesized based on the structure of previously reported TNF CIAM inhibitor F002, which lodges into a defined TNFR1 cavity at the TNF-binding interface, and screened for in vitro efficacy of TNF pathway inhibition (IκB phosphorylation). Compounds were screened for in vivo efficacy in modulating post-traumatic sleep. Compounds were then tested for efficacy in improving functional recovery and verification of cellular mechanism.
Results: Brain-injured mice treated with Compound 7 (C7) or SGT11 slept significantly less than those treated with vehicle, suggesting a therapeutic potential to target neuroinflammation. SGT11 restored cognitive, sensorimotor, and neurological function. C7 and SGT11 significantly decreased cortical inflammatory cytokines 3 h post-TBI.
Conclusions: Using sleep as a bio-indicator of TNF-R-dependent neuroinflammation, we identified C7 and SGT11 as potential therapeutic candidates for TBI.
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Research reported in this manuscript was supported, in part, by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award numbers R21 NS072611 and PCH Mission Support Funds. The generosity of the Diane and Bruce Halle Foundation and NIH fellowship F31-NS090921 supported JLH during the conduct of these studies. RKR was supported by a Science Foundation Arizona Bisgrove Scholarship during the conduct of these studies.
The data sets used and analyzed during the current study are available from the corresponding author upon reasonable request.
Rowe, Rachel K.; Harrison, Jordan L.; Zhang, Hongtao; Bachstetter, Adam D.; Hesson, David P.; O'Hara, Bruce F.; Greene, Mark I.; and Lifshitz, Jonathan, "Novel TNF Receptor-1 Inhibitors Identified as Potential Therapeutic Candidates for Traumatic Brain Injury" (2018). Sanders-Brown Center on Aging Faculty Publications. 107.