A Polysaccharide-Rich Ingredient from Hypericum perforatum L. Ameliorates Depression-like and Post-Traumatic Stress Disorder-like Symptoms in Mouse Models

<b>Background/Objectives</b>: <i>Hypericum perforatum</i> L. (<i>H. perforatum</i>), commonly known as St. John's wort, has been widely used in clinical practice to treat mental disorders. Previous studies and clinical applications have primarily focused on its alcohol-soluble ingredients. Our research was designed to investigate the physicochemical properties, antidepressant-like effects, and anti-post-traumatic stress disorder (PTSD)-like effects of the alcohol-insoluble polysaccharide-rich ingredients from <i>H. perforatum</i>. Meanwhile, the underlying mechanisms were elucidated. <b>Methods</b>: The physicochemical properties of two polysaccharide-rich ingredients, designated as HPP1 and HPP2, were characterized using colorimetric assay, capillary electrophoresis, high-performance gel permeation chromatography, and fourier transform infrared spectroscopy. Behavioral despair tests were conducted to rapidly assess and compare their antidepressant-like effects in mice. Subsequently, behavioral despair mice and foot-shock mice were established to thoroughly explore the impact of HPP2 on depression-like and PTSD-like symptoms. The effects of HPP2 on cerebral pathological changes, neurotrophic factors, and gut microbiota in foot-shock mice were detected through hematoxylin & eosin staining, immunofluorescence staining, and 16S rDNA (V3 + V4 regions) gene sequencing. <b>Results</b>: HPP1 and HPP2 are predominantly composed of arabinose, glucose, galactose, mannose, and galacturonic acid. The molecular weight distribution of HPP1 ranges from 1133 to 67,278 Da, whereas that of HPP2 extends from 1493 to 38,407 Da. Acute pre-treatment with HPP1 or HPP2 (200 mg/kg, i.g.) could reduce mice's immobility in behavioral despair tests, with HPP2 exhibiting superior efficacy. Additionally, both acute and sub-chronic pre-treatment with HPP2 (50, 200, and 800 mg/kg, i.g.) effectively alleviated depression-like symptoms in behavioral despair mice. Prolonged pre-treatment with HPP2 (200 mg/kg, i.g.) also mitigated the slow increase in body weight and behavioral abnormalities in foot-shock mice. Furthermore, HPP2 (200 mg/kg) successfully restored hippocampal histomorphological abnormalities, neurotrophic disturbance, and dysregulation of the gut microbiota in foot-shock mice. <b>Conclusions</b>: HPP2 exerts noteworthy antidepressant-like and anti-PTSD-like impact in mouse models via multiple targets, indicating a potential therapeutic candidate in depression and PTSD therapy.