Pharmacological inhibition of STING reduces neuroinflammation-mediated damage post-traumatic brain injury

Fryer, AL; De Veer, M; Abdullah, A; Mobilio, F; Jobling, A; Moore, Z; Zheng, G; Wong, BX; Taylor, JM; Crack, PJ

Author(s): Fryer, AL; De Veer, M; Abdullah, A; Mobilio, F; Jobling, A; Moore, Z; Zheng, G; Wong, BX; Taylor, JM; Crack, PJ;
Details: Publication Year 2024-05-06,Volume 181,Issue #17,Page 3118-3135
Journal Title: British Journal of Pharmacology
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: Refer to copyright notice on published article.

Creation Date: 2024-05-08 10:06:35

Last Modified: 2024-08-14 11:29:26