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Quercetin Ameliorates Cognitive Impairment in Depression by Targeting HSP90 to Inhibit NLRP3 Inflammasome Activation

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Abstract

Cognitive dysfunction was a common symptom of major depressive disorder (MDD). In previous studies, psychological stress leads to activation and proliferation of microglial cells in different brain regions. Quercetin, a bioflavonoid derived from vegetables and fruits, exerts anti-inflammatory effects in various diseases. To demonstrate the role of quercetin in the hippocampal inflammatory response in depress mice. The chronic unpredictable stress (CUS) depressive mice model built is used to explore the protective effects of quercetin on depression. Neurobehavioral test, protein expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and heat shock protein 90 (HSP90), and cytokines (IL-6, IL-1β, MCP-1, and TNF-α) were assessed. Quercetin ameliorated depressive-like behavior and cognitive impairment, and quercetin attenuates neuroinflammation and by targeting HSP90 to inhibit NLRP3 inflammasome activation. Quercetin inhibited the increase of HSP90 levels in the hippocampus and reverses inflammation-induced cognitive impairment. Besides, quercetin inhibited the increased level of cytokines (IL-6, IL-1β, MCP-1, and TNF-α) in the hippocampus of the depressive model mouse and the increased level of cytokines (IL-6, IL-1β, and MCP-1) in microglia. The current study indicated that quercetin mitigated depressive-like behavior and by targeting HSP90 to inhibit NLRP3 inflammasome activation in microglia and depressive mice model, meanwhile ameliorated cognitive impairment in depression. Quercetin has huge potential for the novel pharmacological efficacy of antidepressant therapy.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank all of our authors for their help and contributions to this project.

Funding

This study was supported by grants from the National Natural Science Foundation of China (No. 82001425), Natural Science Foundation of Jiangsu Province (No. BK20201223), Key Project of Jiangsu Provincial Health Commission (No. ZDB2020019), and Double-Innovation Doctor of Jiangsu Province (No. 2020–30199).

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  1. Department of Laboratory Medicine, Affiliated Hospital of Yangzhou University, Yangzhou, 225012, Jiangsu, China

    Longfei Du, Yi Yang, Shusheng Wu & Yuan Liu

  2. Department of Medicine, Yangzhou University, Yangzhou, 225012, Jiangsu, China

    Xuyuan Fan

  3. Department of the Central Laboratory, Affiliated Hospital of Yangzhou University, Yangzhou, 225012, Jiangsu, China

    Yi Yang

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Contributions

L. D. designed the experiments, data extraction, and analysis. L. D. and X. F. performed in experiments. Y. Y. supervised the work. L. D., X. F., S. W., and Y. L. wrote the manuscript with input from all authors. L. D., Y. Y., and Y. L. contributed to revising it critically for important intellectual content of the review.

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Correspondence to Shusheng Wu or Yuan Liu.

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Du, L., Fan, X., Yang, Y. et al. Quercetin Ameliorates Cognitive Impairment in Depression by Targeting HSP90 to Inhibit NLRP3 Inflammasome Activation. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-03926-x

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