Polygonum sibiricum, with its medicinal and edibility dual properties, has been widely recognized and utilized throughout Chinese history. As a kind of its effective component, Polygonum sibiricum polysaccharides (PSP) have been reported to be a promising novel antidepressant agent. Meanwhile, the precise mechanisms underlying its action remain elusive. The polarization state transition of microglia is intricately linked to neuroinflammation, indicating its crucial involvement in the pathophysiology of depression. Researchers are vigorously pursuing the exploration of this potential treatment strategy, aiming to comprehend its underlying mechanisms. Hence, the current study was designed to investigate the antidepressant mechanisms of PSP via Microglial M1/M2 Polarization, based on the lipopolysaccharide (LPS)-induced BV2 cell activation model. The results indicate that PSP significantly inhibited NO and LDH release and reduced ROS levels in LPS-induced BV2 cells. PSP could significantly reduce the protein expression level of Iba-1, decreased the mRNA levels of TNF-α, IL-1β, and IL-6, and increased the mRNA level of IL-10. PSP also significantly reduced the protein expression level of CD16/32 and increased that of CD206, reduced the mRNA level and fluorescence intensity of iNOS, and increased those of Arg-1. However, PSP pretreatment reversed the alterations of the BDNF/TrkB/CREB and Notch/Hes1 pathways in LPS-induced BV2 cells. These results suggested that PSP exerted the anti-inflammatory effects by inhibiting M1 phenotype polarization and promoting microglia polarization toward the M2 phenotype, and its regulation of microglia M1/M2 polarization may be associated with modulating the BDNF/TrkB/CREB and Notch/Hes1 pathways.

Polysaccharides are one of the main active ingredients of Polygonum sibiricum (PS), which is a food and medicine homolog used throughout Chinese history. The antidepressant-like effects of PSP and its underlying mechanisms remain elusive, especially the regulation of microglial polarization. The current study determined the chemical composition and structural characteristics of PSP. Then, the chronic unpredictable mild stress (CUMS) procedure was carried out on the zebrafish for 5 weeks, and PSP was immersed for 9 days (1 h/d). The body weight of zebrafish was monitored, and behavioral tests, including the novel tank test and light and dark tank test, were performed to evaluate the antidepressant-like effects of PSP. Then, the function of the hypothalamic-pituitary-interrenal (HPI) axis, the levels of peripheral inflammation, neuronal and blood–brain barrier damage in the mesencephalon and telencephalon, and the mRNA expression of M1/M2 phenotype genes in the brain were examined. PSP samples had the typical structural characteristics of polysaccharides, consisting of glucose, mannose, and galactose, with an average Mw of 20.48 kDa, which presented porous and agglomerated morphologies. Compared with untreated zebrafish, the depression-like behaviors of CUMS-induced zebrafish were significantly attenuated. PSP significantly decreased the levels of cortisol and pro-inflammatory cytokines and increased the levels of the anti-inflammatory cytokines in the body of CUMS-induced depressive zebrafish. Furthermore, PSP remarkably reversed the neuronal and blood–brain barrier damage in the mesencephalon and telencephalon and the mRNA expression of M1/M2 phenotype genes in the brain. These findings indicated that the antidepressant-like effects of PSP were related to altering the HPI axis hyperactivation, suppressing peripheral inflammation, inhibiting neuroinflammation induced by microglia hyperactivation, and modulating microglial M1/M2 polarization. The current study provides the foundations for future examinations of PSP in the functional foods of emotional regulation.

: Background: The polysaccharides are one of the main active ingredients of Polygonum sibiricum (PSP), which is a traditional food and medicine homologues in China. The antidepressant-like effects of PSP and its underlying mechanisms remain to be studied in depth, especially the regulation of microglial polarization. Methods: The chemical composition and structural characteristics of PSP was determined firstly. The CUMS procedure was carried out to the zebrafish for 5 weeks and PSP were immersed administration for 9 days (1 h/d). The body weight of zebrafish was monitored and the behavioral tests, including the novel tank test and light and dark tank test, were performed to evaluate the antidepressant-like effects of PSP. Then the function of HPI axis, the levels of peripheral inflammation, neuronal and blood-brain barrier damage in mesencephalon and telencephalon and the mRNA expression of M1/M2 phenotype genes in brain were examined. Results: PSP samples had the typical structure characteristics of polysaccharide, consisting of glucose, mannose and galactose with the average Mw 20.48 kDa, which owned a porous and agglomerated morphology. Compared with untreated zebrafish, the depression-like behaviors of CUMS-induced zebrafish were significantly attenuated. PSP significantly decreased the levels of cortisol and the pro-inflammatory cytokines and increased the levels of the anti-inflammatory cytokines in the body of CUMS-induced depressive zebrafish. Furthermore, neuronal and blood-brain barrier damage in mesencephalon and telencephalon and the mRNA expression of M1/M2 phenotype genes in brain were remarkably reversed by PSP. Conclusion: These findings indicated that the antidepressant-like effects of PSP were related to alter the HPI axis hyperactivation, suppress peripheral inflammation, inhibit neuroinflammation induced by microglia hyperactivation, and modulate microglial M1/M2 polarization. The current study provides foundation to the future exploitation of PSP in the functional foods of emotional regulation.

Polygonum sibiricum is a traditional Chinese food and medicine homologues with multiple active ingredients and extensive bioactive effects. Polygonum sibiricum polysaccharides (PSP) are one of the main active ingredients with the antidepressant activity, meanwhile the specific mechanisms of its action are still unclear. Recently, it is recognized by researchers that microglia play a double-edged role in neuroinflammation and the transformation of M1/M2 microglial phenotypes appears to be a potential therapeutic strategy in depression. Therefore, the present study evaluated the effects of PSP on microglial M1/M2 polarization and the molecular mechanisms were studied based on the lipopolysaccharide (LPS)-induced BV2 cell activation model. The results show that PSP significantly inhibited NO and LDH release and reduced ROS levels in LPS-induced BV2 cells. PSP could significantly reduce the protein expression level of Iba-1, decreased the mRNA levels of TNF-, IL-1 and IL-6, increased the mRNA level of IL-10. PSP also significantly reduced the protein expression level of CD16/32 and increased it of CD206, reduced the mRNA level and fluorescence intensity of iNOS and increased them of Arg-1. However, PSP pretreatment reversed the alterations of BDNF/TrkB/CREB and Notch/Hes1 pathways in LPS-induced BV2 cells. These results suggested that PSP exerted the anti-inflammatory effects by inhibiting M1 phenotype polarization and promoting microglia polarization toward M2 phenotype, and its regulation of microglia M1/M2 polarization may be associated with modulating the BDNF/TrkB/CREB and Notch/Hes1 pathways.