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Puerarin is a flavonoid bioactive component extracted from the Chinese herb radix puerariae, which has been reported to have anti-inflammatory and neuroprotective effects and is a potential drug for the treatment of neuroinflammatory diseases. There is increasing evidence that the gut-liver-brain axis is closely related to neurological disorders. However, studies on the use of puerarin for the treatment of depression based on gut-liver-brain axis-mediated inflammatory injury have not been reported. In the present study, a 4-week chronic restraint stress (CRS) mouse depression model was established. Place the mice in 50 mL centrifuge tubes for restraint. The tubes should be perforated with 15-20 small holes to ensure adequate ventilation. The restraint period is from 9:00 a.m. to 1:00 p.m. daily, during which food and water are withheld. Based on the results of previous studies, the better antidepressant dose of puerarin, 100 mg/kg, was chosen, and fluoxetine was used as a positive control to investigate the intervention effect and potential mechanism of puerarin on depression. All of the aforementioned drugs were administered via oral gavage. Sucrose preference test (SPT), tail suspension test (TST), open field test (OFT), novelty suspended feeding test (NSFT) and forced swimming test (FST) were used to observe the behavioral changes in mice to assess the antidepressant effects. The microbial composition of the intestinal tract was analyzed using 16S rRNA gene sequencing. Histopathological changes in colon and liver were also observed by HE staining method. The levels of lipopolysaccharide (LPS) in colon, serum, liver and prefrontal cortex (PFC) and the levels of 5-hydroxytryptamine (5-HT) in prefrontal cortex were detected by enzyme-linked immunosorbent assay (ELISA). The method was developed for the detection of 5-HT in the prefrontal cortex. The serum levels of glutamate transaminase (AST) and alkaline phosphatase (ALP) were measured by microplate assay. Finally, the expression of brain-derived neurotrophic factor (BDNF), TLR4, MYD88, p-IκB-α, and p-p65 proteins were determined by immunoblotting assay (Western Blot, WB) in mice with PFC. Puerarin was effective in alleviating CRS-induced depression-like behaviors measured in SPT, TST, FST and NSFT in mice. Compared with the CRS model group, puerarin increased the rate of sugar-water preference in the SPT and shortened the cumulative immobility time in the TST and FST as well as the ingestion latency in the NSFT in depressed mice. In addition, puerarin administration ameliorated CRS-induced gut microbiota dysbiosis in mice, elevating the abundance of Lactobacillaceae, Lactobacillus spp. Decreased the relative abundance of Ruminococcaceae, Ruminococcus, Desulfovibrionaceae, and Prevotella spp. Puerarin also reduced LPS, AST and ALP levels, improved damaged colon and liver tissues, inhibited neuroinflammatory damage mediated by the TLR4/MYD88/NF-κB signaling pathway, and up-regulated the levels of 5-HT and BDNF in the prefrontal cortex of the mice, thereby reversing CRS-induced depressive-like behaviors in depressed mice. Puerarin can improve CRS-induced depression in mice by regulating the gut-liver-brain axis and its related molecules. For example, it can regulate CRS-induced intestinal flora disorders and intestinal permeability, thereby reducing systemic LPS levels and the relative levels of AST and ALP, inhibiting the activation of the TLR4/MYD88/NF-κB signaling pathway by LPS, thereby reducing neuroinflammatory damage, and ultimately improving the depressive symptoms of CRS mice.