Pharmacological inhibition of STING reduces neuroinflammation-mediated damage post-traumatic brain injury
- Author(s)
- Fryer, AL; Abdullah, A; Mobilio, F; Jobling, A; Moore, Z; De Veer, M; Zheng, G; Wong, BX; Taylor, JM; Crack, PJ;
- Journal Title
- British Journal of Pharmacology
- Publication Type
- May 6 epub ahead of print
- Abstract
- BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) remains a major public health concern worldwide with unmet effective treatment. Stimulator of interferon genes (STING) and its downstream type-I interferon (IFN) signalling are now appreciated to be involved in TBI pathogenesis. Compelling evidence have shown that STING and type-I IFNs are key in mediating the detrimental neuroinflammatory response after TBI. 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 n-(4-iodophenyl)-5-nitrofuran-2-carboxamide (C-176) in the controlled cortical impact mouse model of TBI in 10- to 12-week-old male mice. Thirty minutes post-controlled cortical impact surgery, a single 750-nmol dose of C-176 or saline (vehicle) was administered intravenously. Analysis was conducted 2 h and 24 h post-TBI. KEY RESULTS: Mice administered C-176 had significantly smaller cortical lesion area when compared to vehicle-treated mice 24 h 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 2 h 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.
- Publisher
- Wiley
- Keywords
- Sting; neurodegeneration; neuroinflammation; traumatic brain injury
- Research Division(s)
- Personalised Oncology
- PubMed ID
- 38710660
- Publisher's Version
- https://doi.org/10.1111/bph.16347
- Open Access at Publisher's Site
https://doi.org/10.1111/bph.16347- Terms of Use/Rights Notice
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Creation Date: 2024-05-08 10:06:35
Last Modified: 2024-05-08 10:23:03