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The antidepressant effects of asperosaponin VI are mediated by the suppression of microglial activation and reduction of TLR4/NF-κB-induced IDO expression

Abstract

Aim

Indoleamine 2,3-dioxygenase 1 (IDO) is responsible for the progression of the kynurenine pathway, which has been implicated in the pathophysiology of inflammation-induced depression. It has been reported that asperosaponin VI (ASA VI) could play a neuroprotective role through anti-inflammatory and antioxidant. In this study, we examined the antidepressant effect of ASA VI in lipopolysaccharide (LPS)-treated mice and further explored its molecular mechanism by looking into the microglial kynurenine pathway.

Methods

To generate the model, LPS (0.83 mg/kg) was administered intraperitoneally to mice. The mice received ASA VI (10 mg/kg, 20 mg/kg, 40 mg/kg, and 80 mg/kg, i.p.) 30 min before LPS injection. Depressive-like behaviors were evaluated based on the duration of immobility in the forced swim test. Microglial activation and inflammatory cytokines were detected by immunohistochemistry, real-time PCR, and ELISA. The TLR4/NF-κB signaling pathway and the expression of IDO, GluA2, and CamKIIβ were also measured by western blotting.

Results

ASA VI exhibited significant antidepressant activity in the presence of LPS on immobility and latency times in the forced swim test. The LPS-induced activation of microglia and inflammatory response were inhibited by ASA VI, which showed a dose-dependent pattern. TLR4/NF-κB signaling pathway also was suppressed by ASA VI in the hippocampus and prefrontal cortex of LPS-treated mice. Furthermore, ASA VI inhibited the increase in IDO protein expression and normalized the aberrant glutamate transmission in the hippocampus and prefrontal cortex caused by LPS administration.

Conclusion

Our results propose a promising antidepressant effect for ASA VI possibly through the downregulation of IDO expression and normalization of the aberrant glutamate transmission. This remedying effect of ASA VI could be attributed to suppress microglia-mediated neuroinflammatory response via inhibiting the TLR4/NF-κB signaling pathway.

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Acknowledgments

We thank Professor Lanping Guo at the Resource Center of the Chinese Academy of Traditional Chinese Medicine for giving us guidance on the experiment and writing. We are grateful to Jun Yu for help in revising the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (81860675), Guizhou Science and Technology Plan Project ([2019]5611), and Department of Science and Technology of Guizhou High-level Innovative Talents ([2018]5638).

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Contributions

JQZ, SNY, and TZ designed the conceptual idea for this study and wrote the manuscript. SNY, YHL, CHX, and CL performed the experiments and analyzed these data. CGY and WKJ contributed new analytical tools and reagents. All the authors participated in the discussion and approved the manuscript as submitted.

Corresponding author

Correspondence to Tao Zhou.

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The authors declare that they have no conflict of interest.

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Zhang, J., Yi, S., Li, Y. et al. The antidepressant effects of asperosaponin VI are mediated by the suppression of microglial activation and reduction of TLR4/NF-κB-induced IDO expression. Psychopharmacology 237, 2531–2545 (2020). https://doi.org/10.1007/s00213-020-05553-5

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  • DOI: https://doi.org/10.1007/s00213-020-05553-5

Keywords

  • Asperosaponin VI
  • Microglia
  • Indoleamine 2,3-dioxygenase
  • NF-κB
  • Glutamate