Anti‐
HMGB1
Antibody Therapy Ameliorates Depression Following Spinal Cord Injury in Rats by Inhibiting Ferroptosis
Zhiwu Wu, Tao Li, Qinglin Zhong, Jinshi Zhang, Yancong Yang, Jinxiang Liu, Xinyun Ye, Qiuhua Jiang, Kaiming Feng, Qianliang Huang ABSTRACT
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.