Metallotoxicity-driven oxidative perturbations in spinal cord injury: Unraveling the pathophysiological nexus between metal-induced redox imbalance and disease severity: A correlational and multivariate analysis.

BACKGROUND: Secondary injury processes, especially oxidative stress and inflammation, are crucial in aggravating neuronal damage and restricting recovery in spinal cord injury (SCI), a crippling neurological disorder. Disruption of metal homeostasis may further amplify redox imbalance by impairing antioxidant defenses and promoting inflammatory pathways; however, integrated clinical evidence linking metal dyshomeostasis with oxidative, nitrosative, and inflammatory biomarkers in human SCI remains limited. OBJECTIVE: To investigate the interrelationships among trace and toxic metal levels, oxidative and nitrosative stress markers, antioxidant defenses, inflammatory cytokines, and neurological severity in patients with SCI. METHODS: This case-control study comprised 105 patients with clinically confirmed SCI and 105 age- and sex-matched healthy controls. Oxidative stress markers (lipid peroxidation, protein carbonyls, nitric oxide), antioxidant enzymes (catalase, Glutathione reductase, glutathione peroxidase, and superoxide dismutase), non-enzymatic antioxidants (vitamins A, C, and E), inflammatory cytokines (IL-6 and TNF-α), and plasma metal concentrations (iron, copper, zinc, selenium, and lead) were quantified using standard biochemical assays, ELISA, and atomic absorption spectrophotometry. Group comparisons were performed using the Mann-Whitney U test, and associations were evaluated using Spearman's rank correlation analysis. Correlation patterns were visualized using clustered heat maps. RESULTS: SCI patients exhibited significantly elevated lipid peroxidation, protein carbonyl content, nitric oxide levels, IL-6, and TNF-α compared with controls (all p < 0.001), indicating pronounced oxidative, nitrosative, and inflammatory stress. Activities of catalase, glutathione peroxidase, and glutathione reductase, as well as levels of vitamins A, C, and E, were significantly reduced, whereas superoxide dismutase activity was increased. Plasma concentrations of essential trace elements (iron, copper, zinc, and selenium) were significantly lower in SCI patients, while lead levels did not differ between groups. Correlation analysis revealed strong positive associations between oxidative stress markers and inflammatory cytokines, and significant inverse correlations with antioxidant enzymes, vitamins, and essential trace elements. Clustered heat maps demonstrated distinct grouping of oxidative and inflammatory markers, opposed by antioxidant and metal-dependent protective systems. CONCLUSION: Spinal cord injury is associated with profound disruption of redox balance, characterized by heightened oxidative and inflammatory stress, impaired antioxidant defenses, and essential trace-element depletion. The strong interrelationships among metal dyshomeostasis, oxidative damage, and inflammation suggest that micronutrient imbalance may actively contribute to secondary injury processes in SCI. Monitoring and targeted restoration of antioxidant capacity and metal homeostasis may represent promising adjunct strategies for mitigating secondary neuronal damage and improving clinical outcomes in SCI.