Background: Blood-spinal cord barrier (BSCB) disruption is a key event after spinal cord injury (SCI), which permits unfavorable blood-derived substances to enter the neural tissue and exacerbates secondary injury. However, limited mechanical impact is usually followed by a large-scale BSCB disruption in SCI. How the BSCB disruption is propagated along the spinal cord in the acute period of SCI remains unclear. Thus, strategies for appropriate clinical treatment are lacking. Methods: A SCI contusion mouse model was established in wild-type and LysM-YFP transgenic mice. In vivo two-photon imaging and complementary studies, including immunostaining, capillary western blotting, and whole-tissue clearing, were performed to monitor BSCB disruption and verify relevant injury mechanisms. Clinically applied target temperature management (TTM) to reduce the core body temperature was tested for the efficacy of attenuating BSCB disruption. Results: Barrier leakage was detected in the contusion epicenter within several minutes and then gradually spread to more distant regions. Membrane expression of the main tight junction proteins remained unaltered at four hours post-injury. Many junctional gaps emerged in paracellular tight junctions at the small vessels from multiple spinal cord segments at 15 min post-injury. A previously unnoticed pathological hemodynamic change was observed in the venous system, which likely facilitated gap formation and barrier leakage by exerting abnormal physical force on the BSCB. Leukocytes were quickly initiated to transverse through the BSCB within 30 min post-SCI, actively facilitating gap formation and barrier leakage. Inducing leukocyte transmigration generated gap formation and barrier leakage. Furthermore, pharmacological alleviation of pathological hemodynamic changes or leukocyte transmigration reduced gap formation and barrier leakage. TTM had very little protective effects on the BSCB in the early period of SCI other than partially alleviating leukocyte infiltration. Conclusions: Our data show that BSCB disruption in the early period of SCI is a secondary change, which is indicated by widespread gap formation in tight junctions. Pathological hemodynamic changes and leukocyte transmigration contribute to gap formation, which could advance our understanding of BSCB disruption and provide new clues for potential treatment strategies. Ultimately, TTM is inadequate to protect the BSCB in early SCI.Keywords: Blood–spinal cord barrier; Hypothermia; Spinal cord injury; Tight junction; Two–photon microscopy.

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