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Pharmacological inhibition of STING reduces neuroinflammation-mediated damage post-traumatic brain injury
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  • Amelia Fryer,
  • Amar Abdullah,
  • Frank Mobilio,
  • Zachery Moore,
  • Gang Zheng,
  • Michael de Veer,
  • Bruce Wong,
  • Juliet Taylor,
  • Peter Crack
Amelia Fryer
The University of Melbourne
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Amar Abdullah
The University of Melbourne
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Frank Mobilio
The University of Melbourne
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Zachery Moore
The University of Melbourne
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Gang Zheng
Monash University
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Michael de Veer
Monash University
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Bruce Wong
The University of Melbourne
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Juliet Taylor
The University of Melbourne
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Peter Crack
The University of Melbourne

Corresponding Author:[email protected]

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Abstract

Background and Purpose: Traumatic brain injury (TBI) remains a major public health concern worldwide with unmet effective treatment. Stimulator of Interferon Genes (STING) protein and its downstream type-I Interferon (IFN) signaling are now appreciated to be involved in TBI pathogenesis. Compelling evidence have shown that STING and type-I IFNs are key in mediating detrimental neuroinflammatory response after TBI, exacerbating outcome. Therefore, pharmacological inhibition of STING presents a viable therapeutic opportunity in combating the detrimental neuroinflammatory response after TBI. Experimental Approach: This study investigated the neuroprotective effects of the small-molecule STING inhibitor C-176 in the controlled-cortical impact (CCI) mouse model of TBI in 10–12-week-old male mice. 30-minutes post-CCI surgery, a single 750nmol dose of C-176 or saline (vehicle) was administered intravenously. Analysis was conducted 2h- and 24h-post TBI. Key Results: Mice administered C-176 had significantly smaller cortical lesion area when compared to vehicle-treated mice 24h post-TBI. Quantitative temporal gait analysis conducted using DigiGait™ showed C-176 administration attenuated TBI-induced impairments in gait symmetry, stride frequency and forelimb stance width. C-176-treated mice displayed a significant reduction in striatal gene expression of pro-inflammatory cytokines TNF-α, IL-1β and CXCL10 compared to their vehicle-treated counterparts 2h post-TBI. Conclusion and Implications: This study demonstrates the neuroprotective activity of C-176 in ameliorating acute neuroinflammation and preventing white matter neurodegeneration post-TBI. This study highlights the therapeutic potential of small-molecule inhibitors targeting STING for the treatment of trauma induced inflammation and neuroprotective potential.
04 Aug 2023Submitted to British Journal of Pharmacology
04 Aug 2023Submission Checks Completed
04 Aug 2023Assigned to Editor
04 Aug 2023Review(s) Completed, Editorial Evaluation Pending
08 Aug 2023Reviewer(s) Assigned
05 Sep 2023Editorial Decision: Revise Minor