Effects of Saikosaponin A on post-traumatic stress disorder-like behaviors, hippocampal monoaminergic neurotransmission, and the NF-κB inflammatory pathway in a rat model.

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition with limited effective treatments. Saikosaponin A (SSa), a bioactive triterpenoid from Bupleurum chinense, exhibits neuroprotective and anti-inflammatory properties, yet its therapeutic potential for PTSD remains unexplored. This study investigated whether SSa ameliorates PTSD-like behaviors in rats and examined the underlying mechanisms. A PTSD rat model was established using single prolonged stress (SPS) combined with footshock(FS). Rats were randomly assigned to control, model, SSa treatment, and fluoxetine-positive control groups. Behavioral assessments included open-field, elevated plus maze, freezing behavior test, and forced swim tests. Hippocampal serotonin (5-HT) levels were measured by high-performance liquid chromatography-mass spectrometry, pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], interleukin-1β [IL-1β]) by enzyme-linked immunosorbent assay (ELISA), and nuclear factor kappa B (NF-κB) p65 protein by was Western blot SSA treatment significantly ameliorated PTSD-like behaviors on days 14 and 21 post-intervention. Mechanistically, SSa restored depleted hippocampal 5-HT levels, reduced pro-inflammatory cytokines expression (TNF-α, IL-6, IL-1β), and suppressed NF-κB p65 activation. These findings demonstrate that SSa exerts therapeutic effect against PTSD-like behavior through dual mechanisms: restoration of hippocampal serotonergic neurotransmission and suppression of NF- κB- mediated neuroinflammation, positioning SSa as a promising candidate for PTSD treatment.