460. HMGB1 contributes to blood-brain barrier disruption and neuronal injury in stress-induced depression

Abstract

Abstract Background Depression is a complex neuropsychiatric disorder, with inflammation and blood-brain barrier (BBB) dysfunction contributing significantly to its pathogenesis. High Mobility Group Box 1 (HMGB1), has been implicated in various inflammatory processes and neurological disorders. However, its role in depression and its underlying mechanisms remain unclear. Aims & Objectives This study aimed to explore the role of HMGB1 in the pathophysiology of depression using a chronic social defeat stress (CSDS) mouse model, and how its expression influences inflammation and neurogenesis in the hippocampus. Additionally, we aimed to assess the clinical relevance of these findings by analyzing HMGB1 levels in depressed adolescents. Method We established the CSDS model and analyzed HMGB1 expression in the hippocampus and prefrontal cortex using Western blotting. We assessed the expression downstream molecular in the hippocampus. Inflammatory cytokine levels were measured using ELISA. HMGB1 was knocked down and overexpressed in the hippocampus of mice, and the impact on the aforementioned pathways, inflammation, and behavior was evaluated. Neuronal apoptosis was assessed using Nissl staining. Immunofluorescence was used for further validation. Clinical serum samples from depressed and healthy adolescents were analyzed for HMGB1 levels. Results HMGB1 expression was significantly higher in the hippocampus compared to the prefrontal cortex. In the hippocampus, changes in HMGB1 expression were associated with alterations in inflammation and neuronal survival. Inflammatory cytokine levels in the hippocampus also showed significant differences. Modulating HMGB1 expression in the hippocampus led to changes in inflammatory cytokine levels, neuronal apoptosis, integrity of the BBB and depressive-like behaviors in the mice. Additionally, serum HMGB1 levels were significantly higher in depressed adolescents compared to healthy controls. Discussion & Conclusions This study demonstrates that HMGB1 plays a key role in depression related neuronal oxidative stress, emphasizing its potential as an intervention target to mitigate neuronal oxidative damage in depression. Additionally, the elevated serum HMGB1 levels observed in depressed adolescents suggest that HMGB1 could serve as a promising biomarker for depression.