Neutrophil Elastase Inhibitor Sivelestat Attenuates Secondary Injury After Spinal Cord Contusion in Rats by Modulating Neuroinflammation, Oxidative Stress and Apoptosis

Background: Traumatic spinal cord injury (SCI) often leads to permanent neurological deficits. Secondary injury processes, especially neuroinflammation, oxidative stress, and apoptosis, are key drivers of progressive tissue loss. Sivelestat sodium is a selective neutrophil elastase (NE) inhibitor with anti-inflammatory effects in systemic inflammatory response syndrome and acute lung injury, but its role in traumatic SCI and its interaction with methylprednisolone (MP) remain unclear.
Methods: A thoracic contusive SCI model was established in adult male Sprague–Dawley rats using a modified Allen weight-drop method at T10. Animals were randomly assigned to six groups (n = 6 each): sham, SCI model, sivelestat (Siv), low-dose MP (L-MP, 20 mg/kg), high-dose MP (H-MP, 30 mg/kg), and L-MP plus sivelestat (L-MP+Siv). Sham rats underwent laminectomy only. Sivelestat (4.8 mg/kg, intraperitoneally) was started 1 h after SCI and continued once daily for 7 days (Siv and L-MP+Siv). MP was given as a single dose within 1 h after SCI. Sensory recovery was assessed using Reuter scores on days 1, 3, 5, and 7. On day 7, T10 spinal cord segments were harvested. Interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-10 (IL-10) were measured by ELISA. Oxidative stress was evaluated by superoxide dismutase (SOD) activity and malondialdehyde (MDA). Apoptosis was assessed by TUNEL staining and apoptotic index (AI).
Results: Compared with sham, SCI markedly increased IL-1β and TNF-α and decreased IL-10, reduced SOD activity, and elevated MDA (all P < 0.01), indicating pronounced neuroinflammation and oxidative stress. Sivelestat significantly lowered IL-1β and TNF-α, raised IL-10, enhanced SOD, and reduced MDA versus the SCI model group (all P < 0.01). Low- and high-dose MP produced similar improvements. H-MP and L-MP+Siv showed the greatest reductions in IL-1β, TNF-α, and MDA and the highest IL-10 and SOD levels, outperforming sivelestat alone and L-MP (P < 0.05). TUNEL staining showed a significant alteration in AI in the SCI model group versus sham (P < 0.01); H-MP and L-MP+Siv significantly reduced AI compared with the SCI model (P < 0.05). Reuter scores improved from days 3–7 in all treatment groups, with the best recovery in H-MP and L-MP+Siv (P < 0.05).
Conclusions: Sivelestat promotes sensory recovery and attenuates neuroinflammation and oxidative stress after SCI, accompanied by modulation of apoptosis. Combining low-dose MP with sivelestat provides stronger anti-inflammatory, antioxidant, and anti-apoptotic effects than either drug alone, supporting NE inhibition plus reduced-dose MP as a promising multi-target strategy to limit secondary injury after SCI.