Polygalic acid produces rapid antidepressant effects via modulation of hippocampal inflammation and brain-derived neurotrophic factor expression in mice

Major depressive disorder represents a critical global health burden with limited rapid-acting therapeutic options. This study investigated the natural triterpenoid saponin polygalic acid for rapid antidepressant efficacy and its mechanistic relationship with neuroinflammation. In male C57BL/6 mice subjected to chronic unpredictable mild stress, acute intraperitoneal administration of polygalic acid (30 mg/kg) produced robust behavioral improvements 2 h postinjection ( n  = 8–10 per group), as evidenced by reduced immobility in the tail suspension and forced swimming tests (indicative of enhanced stress coping), restored sucrose preference (reversal of anhedonia), and decreased latency to feed in the novelty-suppressed feeding test (improved motivation) – all without altering locomotor activity or anxiety-like behavior in the open field test. Mechanistically, polygalic acid concurrently suppressed hippocampal nuclear factor-kappa B activation and elevated antiinflammatory cytokines (tumor necrosis factor-beta and interleukin-10) and brain-derived neurotrophic factor (BDNF). To causally examine whether inflammatory status gates polygalic acid’s efficacy, coadministration of lipopolysaccharide, which induces acute systemic inflammation, completely abolished polygalic acid’s behavioral and molecular effects. These findings demonstrate that polygalic acid produces ketamine-like rapid antidepressant effects specifically through the resolution of chronic neuroinflammatory dysregulation and BDNF restoration. However, the presence of acute inflammatory activation nullifies its therapeutic efficacy, establishing neuroinflammatory context as a critical determinant of treatment response. While limited to male subjects and acute (2-h) assessment, this work identifies polygalic acid as a promising rapid-acting antidepressant candidate and underscores the therapeutic importance of patient stratification based on inflammatory biomarkers when targeting the nuclear factor-kappa B–BDNF axis.