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

Abstract

Background and PurposeTraumatic 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 ApproachThis 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 ResultsMice 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 ImplicationsThis 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.