Microglial activation and neuroinflammation induced by amyloid β (Aβ) play pivotal roles in Alzheimer's disease (AD) pathogenesis. Astragaloside IV (AS-IV) is one of the major active compounds of the traditional Chinese medicine Astmgali Radix. It has been reported that AS-IV could protect against Aβ-induced neuroinflammation and cognitive impairment, but the underlying mechanisms need to be further clarified. In this study, the therapeutic effects of AS-IV were investigated in an oligomeric Aβ (oAβ) induced AD mice model. The effects of AS-IV on microglial activation, neuronal damage and NADPH oxidase expression were further studied. Different doses of AS-IV were administered intragastrically once a day after intracerebroventricularly oAβ injection. Results of behavioral experiments including novel object recognition (NOR) test and Morris water maze (MWM) test revealed that AS-IV administration could significantly ameliorate oAβ-induced cognitive impairment in a dose dependent manner. ELISA results showed that increased levels of ROS, TNF-α, IL-1β and IL-6 in hippocampal tissues induced by oAβ injection were remarkably inhibited after AS-IV treatment. OAβ induced microglial activation and neuronal damage was significantly suppressed in AS-IV-treated mice brain, observed in immunohistochemistry results. Furthermore, oAβ upregulated protein expression of NADPH oxidase subunits gp91phox, p47phox, p22phox and p67phox were remarkably reduced by AS-IV in western blotting assay. These results revealed that AS-IV could ameliorate oAβ-induced cognitive impairment, neuroinflammation and neuronal damage, which were possibly mediated by inhibition of microglial activation and down-regulation of NADPH oxidase protein expression. Our findings provide new insights of AS-IV for the treatment of neuroinflammation related diseases such as AD.
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by memory loss and cognitive dysfunction in the elderly, with amyloid-beta (Aβ) deposition and hyperphosphorylation of tau protein as the main pathological feature. Nuclear factor 2 (Nrf2) is a transcription factor that primarily exists in the cytosol of hippocampal neurons, and it is considered as an important regulator of autophagy, oxidative stress, and inflammation. Total saikosaponins (TS) is the main bioactive component of Radix bupleuri (Chaihu). In this study, it was found that TS could ameliorate cognitive dysfunction in APP/PS1 transgenic mice and reduce Aβ generation and senile plaque deposition via activating Nrf2 and downregulating the expression of β-secretase 1 (BACE1). In addition, TS can enhance autophagy by promoting the expression of Beclin-1 and LC3-II, increasing the degradation of p62 and NDP52 and the clearance of phosphorylated tau (p-tau), and reducing the expression of p-tau. It can also downregulate the expression of nuclear factor-κB (NF-κB) to inhibit the activation of glial cells and reduce the release of inflammatory factors. In vitro experiments using PC12 cells induced by Aβ, TS could significantly inhibit the aggregation of Aβ and reduce cytotoxicity. It was found that Nrf2 knock-out weakened the inhibitory effect of TS on BACE1 and NF-κB transcription in PC12 cells. Moreover, the inhibitory effect of TS on BACE1 transcription was achieved by promoting the binding of Nrf2 and the promoter of BACE1 ARE1. Results showed that TS downregulated the expression of BACE1 and NF-κB through Nrf2, thereby reducing the generation of Aβ and inhibiting neuroinflammation. Furthermore, TS can ameliorate synaptic loss and alleviate oxidative stress. In gut microbiota analysis, dysbiosis was demonstrated in APP/PS1 transgenic mice, indicating a potential link between gut microbiota and AD. Furthermore, TS treatment reverses the gut microbiota disorder in APP/PS1 mice, suggesting a therapeutic strategy by remodeling the gut microbe. Collectively, these data shows that TS may serve as a potential approach for AD treatment. Further investigation is needed to clarify the detailed mechanisms underlying TS regulating gut microbiota and oxidative stress.
Radix Bupleuri is a traditional medicine widely used in China and other Asian countries. Phytochemistry and pharmacology study reveal that saikosaponins(SSs) are the main bioactive compounds in Radix Bupleuri. SSs are complex compounds composed of triterpene aglycone and carbohydrate part containing 1-13 monosaccharides, which can be divided into seven types based on their structural characteristics. Many different kinds of SSs have been isolated from plants of Bupleurum L. SSs show a variety of biological activities, such as central nervous system protection, liver protection, antivirus, anti-tumor, anti-inflammation, hormone-like effects, and immune regulation functions. Due to their broad activity and favorable safety profile, SSs attract an increasing amount of attention in recent years. In this review, the structures of 86 SSs are summarized based on the different aglycones due to the diverse structures of saikosaponin(SS). The pharmacological effects and related mechanism of SSs are thoroughly reviewed, and perspectives for future research are further discussed.
Alzheimer's disease (AD) is the most common neurodegenerative disease associated with aging. Bupleurum smithii Wolff. is a Chinese folk medicine used to reduce fever and inflammation. Regarding the key role of neuroinflammation in AD pathogenesis, it was speculated that B. smithii may be the source of compounds that treat AD through anti-inflammatory effects. This study aimed to investigate the effects of saikogenin F, a natural active ingredient from B. smithii, on cognition impairment and neuroinflammation in AD mice induced by amyloid β (Aβ). The AD mice model was established by intracerebroventricular (i.c.v.) injection of Aβ, and different doses of saikogenin F (10, 20, and 40 mg/kg) were intragastrically administrated once daily. Results of behavioral experiments, including the novel object recognition (NOR) test, Y-maze test, and Morris water maze (MWZ) test, showed that saikogenin F could ameliorate Aβ-induced cognition impairment in AD mice. Enzyme linked immunosorbent assay (ELISA) results showed that tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and reactive oxygen species (ROS) levels in hippocampal tissue increased after Aβ injection, while saikogenin F could significantly reduce the concentrations of these inflammatory factors. Western blotting results revealed that the Aβ-induced reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits protein expression in mice hippocampus was remarkably downregulated by saikogenin F. Results of Iba-1 immunohistochemical staining showed that saikogenin F could effectively inhibit Aβ-induced activation of microglia in vivo. These results suggested that saikogenin F could relieve Aβ-induced cognitive impairment via inhibiting neuroinflammation and microglial activation. These effects may be achieved by inhibiting the expression of the NADPH oxidase subunits gp91phox and p47phox.
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