Corydalis yanhusuo Polysaccharides regulates HPA-axis mediated microglia activation and inhibits astrocyte A1 transformation to improve depression-like behavior.

Depression is a common emotional disorder characterized by persistent low mood and decreased interest. Corydalis yanhusuo polysaccharides (CYP) are extracts from Corydalis yanhusuo, which have the effects of promoting blood circulation, relieving pain, anti-inflammation, and neuroprotection. This study investigates the effects and its underlying mechanisms of CYP in a chronic unpredictable mild stress (CUMS)-induced depression model using C57BL/6J mice. After 4 weeks of CYP treatment, the depressive behavior of mice was observed, and Nissl staining, H&E staining, and immunofluorescence were performed. The hypothalamic-pituitary-adrenal (HPA) axis factors levels were determined by enzyme-linked immunosorbent assay. Western blotting was used to detect protein expression. The results showed that CYP treatment improved depression-like behaviors in mice that received CUMS and ameliorated pathological damage the hippocampus and synaptic damage via regulating the expression of NeuN, SYP, and PSD95 proteins. CYP also reduced neuroinflammation by decreasing the expression of IL-1β, IL-18, NLRP3, and Caspase-1. In addition, CYP reduced adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone (CRH), corticosterone (CORT), corticotropin releasing factor (CRF), mineralocorticoid receptor (MR) levels, and increased glucocorticoid receptor (GR) levels. Furthermore, CYP could regulate microglial activation and transform A1 astrocytes into neuroprotective A2 astrocytes, thereby mitigating neuronal damage by decreasing the expression of complement C3 (C3) and ionized calcium-binding adaptor molecule 1 (Iba-1), while increasing the expression of S100A10. However, CORT treatment significantly reversed above changes and aggravated depressive behavior in mice. In conclusion, CYP could improve CUMS-induced depression-like behaviors by regulating HPA axis-mediated microglial activation and inhibiting A1 transformation of astrocytes.