Novel TNF receptor-1 inhibitors identified as potential therapeutic candidates for traumatic brain injury
AuthorRowe, Rachel K.
Harrison, Jordan L.
Bachstetter, Adam D.
Hesson, David P.
O’Hara, Bruce F.
Greene, Mark I.
AffiliationUniv Arizona, Coll Med Phoenix, Dept Child Hlth
Univ Arizona, Coll Med Phoenix, Basic Med Sci
MetadataShow full item record
PublisherBIOMED CENTRAL LTD
CitationRowe, R. K., Harrison, J. L., Zhang, H., Bachstetter, A. D., Hesson, D. P., O'Hara, B. F., ... Lifshitz, J. (2018). Novel TNF receptor-1 inhibitors identified as potential therapeutic candidates for traumatic brain injury. Journal of Neuroinflammation, 15(1), . DOI: 10.1186/s12974-018-1200-y
JournalJOURNAL OF NEUROINFLAMMATION
Rights© The Author(s). 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractBackground: 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 (I.B 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.
VersionFinal published version
SponsorsNational Institute of Neurological Disorders and Stroke of the National Institutes of Health [R21 NS072611]; PCH Mission Support Funds; Diane and Bruce Halle Foundation; NIH [F31-NS090921]; Science Foundation Arizona Bisgrove Scholarship
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