Novel TNF receptor-1 inhibitors identified as potential therapeutic candidates for traumatic brain injury

Rachel K. Rowe, Jordan L. Harrison, Hongtao Zhang, Adam D. Bachstetter, David P. Hesson, Bruce F. O'Hara, Mark I. Greene, Jonathan Lifshitz

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number154
JournalJournal of Neuroinflammation
Volume15
Issue number1
DOIs
StatePublished - May 22 2018
Externally publishedYes

Fingerprint

Tumor Necrosis Factor Receptors
Sleep
Tumor Necrosis Factor-alpha
Brain
Therapeutics
Receptors, Tumor Necrosis Factor, Type I
Cytokines
Inflammation
Wounds and Injuries
Brain Injuries
Traumatic Brain Injury
Head
Phosphorylation
Morbidity
Research
Pharmaceutical Preparations

Keywords

  • Concussion
  • Cytokines
  • Diffuse brain injury
  • Midline fluid percussion
  • Mouse
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Novel TNF receptor-1 inhibitors identified as potential therapeutic candidates for traumatic brain injury. / Rowe, Rachel K.; Harrison, Jordan L.; Zhang, Hongtao; Bachstetter, Adam D.; Hesson, David P.; O'Hara, Bruce F.; Greene, Mark I.; Lifshitz, Jonathan.

In: Journal of Neuroinflammation, Vol. 15, No. 1, 154, 22.05.2018.

Research output: Contribution to journalArticle

Rowe, Rachel K. ; Harrison, Jordan L. ; Zhang, Hongtao ; Bachstetter, Adam D. ; Hesson, David P. ; O'Hara, Bruce F. ; Greene, Mark I. ; Lifshitz, Jonathan. / Novel TNF receptor-1 inhibitors identified as potential therapeutic candidates for traumatic brain injury. In: Journal of Neuroinflammation. 2018 ; Vol. 15, No. 1.
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AU - Harrison, Jordan L.

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AU - Hesson, David P.

AU - O'Hara, Bruce F.

AU - Greene, Mark I.

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AB - 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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