Selenium-Containing bioactive peptides attenuate spinal cord injury by inhibiting Blood-Spinal cord barrier disruption and neuronal ferroptosis.

BACKGROUND: (SeSP) have emerged as potential neuroprotective agents. However, their therapeutic efficacy and underlying molecular mechanisms in the context of SCI have not been fully elucidated. METHODS: To address this, we utilized a clinically relevant rat model of T10 contusion SCI to evaluate the restorative effects of SeSP. We systematically assessed neurological function recovery and employed a combination of immunofluorescence, western blotting, and biochemical assays to investigate BSCB integrity, neuroinflammatory responses, oxidative stress markers, and ferroptosis regulatory networks within the injured spinal cord. RESULTS: SeSP administration significantly promoted locomotor recovery and preserved BSCB integrity by restoring the expression of key tight junction proteins (ZO-1, Occludin, and Claudin-5) and suppressing matrix metalloproteinase-9 (MMP-9) activity. Furthermore, SeSP treatment attenuated neuronal loss, inhibited microglial activation, and reduced the secretion of pro-inflammatory cytokines. Mechanistically, SeSP mitigated lipid peroxidation and DNA damage while exerting a potent anti-ferroptotic effect, as evidenced by the upregulation of GPX4, FTH1, and SLC7A11, and the downregulation of TXNIP, ACSL1, and DMT1. CONCLUSION: Our findings demonstrate that SeSP exerts robust neuroprotection in SCI primarily by maintaining BSCB integrity and inhibiting oxidative stress-driven neuronal ferroptosis. These data identify SeSP as a promising therapeutic candidate for mitigating secondary injury and enhancing functional recovery following spinal cord trauma.