Antidepressant and anxiolytic effects of Wuling Capsule in CSDS mice: Alleviating HPA axis hyperactivity via the Nesfatin-1/NF-κB signaling pathway.

Ethnopharmacological Relevance: Wuling capsule, composed of the traditional Chinese medicine Wuling mycelia powder, is made by fermenting and processing Xylaria nigripes (Kl.) Sacc. Clinically, it is commonly used to alleviate depression and anxiety. However, the mechanisms through which Wuling capsule exerts its therapeutic benefits have not been clearly defined.
Aim of the Study: This study aims to elucidate the mechanisms by which Wuling capsule alleviates depression and anxiety like behaviors induced by chronic social defeat stress (CSDS) in mice.
Materials and Methods: High-performance liquid chromatography-tandem mass spectrometry system was used to identify the components of the Wuling capsule. Mice were subjected to CSDS to induce depression and anxiety-like behaviors. The expression of hypothalamic corticotropin-releasing hormone (CRH) and Nesfatin-1, as well as serum levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were quantified. Behavioral assessments included the open field test, elevated plus maze, sucrose preference test, and forced swim test to evaluate depression and anxiety levels. Specific manipulation of Nesfatin-1 in the paraventricular nucleus of the hypothalamus (PVN) or cells was achieved through stereotaxic virus injection or plasmid transfection. Intracerebral cannula implantation was used for PVN-specific drug administration.
Results: A total of 123 different components were identified in Wuling capsule. CSDS induced depression and anxiety-like behaviors in mice, along with hyperactivation of the HPA axis, increased hypothalamic Nesfatin-1 levels, and elevated nuclear factor kappa-B (NF-κB) phosphorylation. Overexpression of Nesfatin-1 in the hypothalamus mimicked the effects of CSDS. Conversely, knockdown of hypothalamic Nesfatin-1 or PVN-specific administration of Nesfatin-1 antibody or NF-κB antagonist mitigated CSDS-induced depression and anxiety-like behaviors and hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. In neuroblastoma-2a (N2a) cells, overexpression of Nesfatin-1 led to increased NF-κB phosphorylation and CRH levels, whereas knockdown of Nesfatin-1 produced the opposite effects. Treatment with Wuling capsule alleviated CSDS-induced depression and anxiety-like behaviors, HPA axis hyperactivity, and activation of the hypothalamic Nesfatin-1/NF-κB pathway.
Conclusions: The hypothalamic Nesfatin-1/NF-κB pathway plays a significant role in depression by modulating the HPA axis and is involved in the antidepressant and anxiolytic effects of Wuling capsule.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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