Forced running attenuates depression-like behavior and hippocampal inflammatory response in mice induced by Chronic Unpredictable Mild Stress

Introduction: As a late proinflammatory factor, the role of High mobility group box 1 (HMGB-1) in nervous system inflammation has been widely studied. The inflammatory response mediated by HMGB-1 plays an important role in the pathophysiological mechanism of depression. This study aimed to investigate the antidepressant effects of forced running on chronic unpredictable mild stress (CUMS) mice by examining the impact on hippocampal HMGB-1. Methods: The experiment included a comparison with the traditional broad-spectrum antidepressant fluoxetine to evaluate the potential benefits of forced exercise or combined therapy. Mice were divided into different groups - control, forced running + fluoxetine (FR+FLU), CUMS, CUMS + forced running (CUMS+FR), CUMS + fluoxetine (CUMS+FLU), and CUMS + forced running + fluoxetine combined therapy (CUMS+FR+FLU). The study used the tail suspension test (TST), forced swimming test (FST), and sucrose preference test (SPT) to assess depression-like behavior. Following the experiment, the levels of hippocampal HMGB-1 and associated proteins and cytokines were measured. Results: The results revealed that four weeks of forced running significantly attenuated depression-like behavior and reduced the expression of HMGB-1-associated inflammatory proteins and cytokines in CUMS mice. Conversely, fluoxetine showed limited effectiveness in reversing depression-like behavior but demonstrated a reduction in the expression of hippocampal HMGB-1-associated inflammatory proteins and cytokines. The combined therapy also exhibited significant antidepressant effects and reduced levels of HMGB-1-associated inflammatory proteins and cytokines, with a faster response compared to forced running alone. Conclusion: Forced running may offer potential benefits in modulating the anti-inflammatory response associated with HMGB-1, providing insights into the potential therapeutic role of physical exercise in managing depression.