The Matrine Derivative MASM Alleviates LPS-Induced Depressive-Like Behavior in Mice by Modulating Hippocampal Inflammation, Oxidative Stress, and Autophagy.

BACKGROUND: Previous studies have demonstrated a significant association between neuroinflammation and major depressive disorder (MDD). (6aS,10S,11aR,11bR,11cS)-10-methylamino-dodecahydro-3a,7a-diaza-benzo(de)anthracene-8-thione (MASM), a derivative of matrine, has recently been shown to display anti-inflammatory properties. However, its effects on lipopolysaccharide (LPS)-induced depression and the underlying mechanisms remain unexplored. This study aimed to assess the effects of MASM on depressive-like behaviors induced by LPS and to investigate the potential mechanisms involved. METHODS: Following intraperitoneal injection of LPS (0.83 mg/kg), MASM was administered. Depressive-like behaviors were assessed through the forced swim test (FST) and tail suspension test (TST). To further explore the mechanisms, LPS-induced BV2 microglial cell models were established. Enzyme-linked immunosorbent assay (ELISA) was used to quantify the expression of TNF-α and high mobility group box 1 (HMGB1), while immunoblotting was performed to assess heme oxygenase-1 (HO-1), sirtuin 1 (SIRT-1), p62, and microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate (LC3-II) expression. Reactive oxygen species (ROS) levels were evaluated using flow cytometry. RESULTS: MASM pretreatment markedly ameliorated acute depressive-like behaviors in LPS-treated mice and upregulated HO-1 expression in the hippocampus. In LPS-stimulated BV2 cells, MASM reduced the levels of proinflammatory markers TNF-α and HMGB1. Furthermore, MASM mitigated LPS-induced oxidative stress, as evidenced by increased ATP, HO-1, and SIRT-1 levels, along with decreased ROS levels. MASM also restored autophagic function, demonstrated by increased LC3-II expression and reduced p62 levels. CONCLUSION: These findings suggests that MASM alleviates LPS-induced neuroinflammation and acute depressive-like behaviors, possibly by reducing oxidative stress and promoting autophagy.