Specific alterations of reactive species interactome markers reflect recovery after mild traumatic brain injury

Recovery from mild traumatic brain injury (mTBI) is believed to be mediated by the secondary injury response with oxidative stress (OS) playing a central role. Previous studies have largely examined isolated OS markers, yielding inconsistent results. This study adopts a more integrated approach by investigating various components of the reactive species interactome (RSI), a conceptual framework that captures the dynamic interplay of redox components, to better understand the role of OS in the recovery trajectory after mTBI. Twenty-two RSI components were measured in plasma obtained from 65 patients with mTBI in the acute phase (<24 h) and subacute phase (four to six weeks) post-injury and 25 healthy controls (HC). Principal component analysis (PCA) was conducted to identify a subset of RSI markers capable of distinguishing between patients with mTBI and HC. Associations between RSI profiles and functional recovery at six months post-injury, as measured by the Glasgow Outcome Scale Extended, were assessed. Trends (uncorrected P < 0.05) towards increases of hydrogen sulfide (H₂S) and glutathione and decreases for zinc and peroxynitrite in patients with acute mTBI were observed. Across recovery groups, patients with complete recovery had significantly higher levels of acutely measured catalase (P = 0.002, r_rb = 0.45) and lower levels of peroxynitrite (P = 0.003, r_rb = -0.43) than patients with incomplete recovery. Subject component scores obtained from the varimax rotated PCA component three (RC3) distinguished mTBI from HC and patients with complete functional recovery from patients with incomplete functional recovery. Strong positive loaders of RC3 included elevated levels of H₂S, circulating ATP, and malondialdehyde, while loadings of calcium, zinc and peroxynitrite contributed negatively to this component. Our findings highlight a pattern of RSI component alterations associated with recovery following mTBI. These findings underscore the complexity of the redox response after mTBI and highlight potential therapeutic targets, including modulation of H₂S, catalase activity and zinc homeostasis.