Anti-HMGB1 Antibody Therapy Ameliorates Depression Following Spinal Cord Injury in Rats by Inhibiting Ferroptosis

Depression following spinal cord injury (D-SCI) refers to a depressive state that occurs in an individual after a major spinal cord injury (SCI), characterized mainly by low mood and reduced interest. This study aims to investigate the regulatory role of anti-HMGB1 antibody in the depressive-like behaviour of D-SCI rats and to explore its underlying mechanisms. A depression model was established in rats 5 weeks after SCI. The expression of HMGB1 and ferroptosis markers (MDA, GSH and iron ion deposition) in the hippocampus were examined in both the sham group and the D-SCI group. Subsequently, D-SCI rats were treated with an anti-HMGB1 antibody, and the depression-like behaviours of each group were assessed using open field and sucrose preference tests. Ferroptosis levels in the hippocampus, as well as the expression of ferroptosis-related proteins (ACSL4, SLC7A11 and GPX4), were also investigated. The co-localization of HMGB1 and NeuN in the rat hippocampus was detected by immunofluorescence double staining. Furthermore, at the cellular level, the effect of the anti-HMGB1 antibody on Erastin-induced ferroptosis in rat hippocampal neurons was analysed. The results indicated that compared to the sham group, the levels of HMGB1 and ferroptosis in the hippocampus of rats in the D-SCI group were significantly elevated. Administering anti-HMGB1 antibody to D-SCI rats could significantly augment their activity distance, movement speed and sucrose preference rate, while also suppressing the ferroptosis level and the expression of ferroptosis-related proteins in the hippocampus. Moreover, HMGB1 and NeuN were co-expressed in the rat hippocampus. The results from primary rat hippocampal neurons indicated that anti-HMGB1 antibody could inhibit erastin-induced ferroptosis in rat hippocampal neurons. Taken together, anti-HMGB1 antibody therapy can ameliorate depressive behaviour in D-SCI rats; the possible mechanism may involve the inhibition of ferroptosis in hippocampal neurons.