Polygalic acid produces rapid antidepressant effects via modulation of hippocampal inflammation and brain-derived neurotrophic factor expression in mice.
{"title":"Polygalic acid produces rapid antidepressant effects via modulation of hippocampal inflammation and brain-derived neurotrophic factor expression in mice.","authors":"Jinjin Xie, Jie Dong, Haixiu Liao, Shuyan Liu, Zhenni He, Chen Zeng","doi":"10.1097/FBP.0000000000000890","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":8832,"journal":{"name":"Behavioural Pharmacology","volume":" ","pages":"210-220"},"PeriodicalIF":1.4000,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Behavioural Pharmacology","FirstCategoryId":"102","ListUrlMain":"https://doi.org/10.1097/FBP.0000000000000890","RegionNum":4,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/8/11 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"BEHAVIORAL SCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍：
Behavioural Pharmacology accepts original full and short research reports in diverse areas ranging from ethopharmacology to the pharmacology of schedule-controlled operant behaviour, provided that their primary focus is behavioural. Suitable topics include drug, chemical and hormonal effects on behaviour, the neurochemical mechanisms under-lying behaviour, and behavioural methods for the study of drug action. Both animal and human studies are welcome; however, studies reporting neurochemical data should have a predominantly behavioural focus, and human studies should not consist exclusively of clinical trials or case reports. Preference is given to studies that demonstrate and develop the potential of behavioural methods, and to papers reporting findings of direct relevance to clinical problems. Papers making a significant theoretical contribution are particularly welcome and, where possible and merited, space is made available for authors to explore fully the theoretical implications of their findings. Reviews of an area of the literature or at an appropriate stage in the development of an author’s own work are welcome. Commentaries in areas of current interest are also considered for publication, as are Reviews and Commentaries in areas outside behavioural pharmacology, but of importance and interest to behavioural pharmacologists. Behavioural Pharmacology publishes frequent Special Issues on current hot topics. The editors welcome correspondence about whether a paper in preparation might be suitable for inclusion in a Special Issue.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
