Diosmin Attenuates PTSD-like Behaviors and Hippocampal Astrocyte Alterations with Reduced STAT1 and CXCL9 Expression in an SPS&S Mouse Model

Diosmin is a citrus-derived flavone glycoside with anti-inflammatory activity in preclinical models. This study aimed to investigate the effects of diosmin on PTSD-like behaviors, astrocyte morphology, and the expression of STAT1 and CXCL9 in a single prolonged stress and shock (SPS&S) mouse model, and to assess whether Stat1 knockdown could mimic diosmin’s effects in primary astrocytes. Male C57BL/6J mice were assigned to the control, SPS&S, and SPS&S + diosmin groups and underwent 14 days of treatment. Behavioral assessments included open-field and elevated plus-maze tests, alongside cue- and context-associated fear tests, complemented by GFAP-based morphometry, immunofluorescence, Western blotting, serum cytokine assays, hippocampal RNA sequencing, and quantitative reverse-transcription PCR (qRT-PCR). The results indicated that diosmin significantly enhanced exploratory behavior and reduced fear responses compared to SPS&S alone, alongside notable alterations in hippocampal astrocyte morphology and a shift in cytokine profiles, with decreased pro-inflammatory cytokines and increased anti-inflammatory markers. RNA sequencing revealed 297 differentially expressed genes, particularly highlighting the roles of Stat1 and Cxcl9, both of which were significantly downregulated upon diosmin treatment. Furthermore, diosmin modulated astrocyte responses to inflammatory stimuli in primary cultures. These findings suggest that diosmin exerts protective effects against PTSD-like symptoms by regulating astrocytic function and immune-related pathways, with STAT1 signaling serving as a key but non-exclusive downstream mechanism underlying its therapeutic actions. Future studies should further elucidate the full spectrum of associated pathways to advance the development of targeted interventions for PTSD.