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Xanthohumol improves cognitive impairment by regulating miRNA-532-3p/Mpped1 in ovariectomized mice

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Abstract

Rationale

Studies have shown the potential neuroprotective effect of xanthohumol, while whether xanthohumol has the ability of repairing cognitive impairment and its underlying mechanism still remains obscure.

Objectives

To unravel the mechanism of xanthohumol repairing cognitive impairment caused by estrogen deprivation.

Methods

C57BL/6 J female mice that underwent bilateral ovariectomy to establish cognitive decline model were randomly divided into three xanthohumol-treated groups and a saline-treated model group. For identifying the neuroprotective function of xanthohumol, Morris water maze (MWM) test and open field test (OFT) were conducted. After extracting total RNA of mouse hippocampus of different groups, mRNA-seq and microRNA (miRNA)-seq analysis were performed, and the differentially expressed miRNAs (DEMIs) and their target genes were further validated by qPCR. MiR-532-3p and its downstream gene Mpped1 were screened as targets of xanthohumol. Influence of miR-532-3p/Mpped1 to cognitive ability was examined via MWM test and OFT after stereotactic brain injection of Mpped1 overexpressed adeno-associated virus. The regulation of miR-532-3p on Mpped1 was confirmed in hippocampal neuronal cell line HT22 by luciferase reporter gene assay.

Results

Xanthohumol treatment reversed the cognitive decline of OVX mice according to behavioral tests. By comparing miRNA levels of xanthohumol-treated groups with saline-treated group, we found that the main changed miRNAs were miR-122-5p, miR-532-3p, and miR-539-3p. Increased miR-532-3p in OVX mice was suppressed by xanthohumol treatment. Furthermore, the downstream gene of miR-532-3p, Mpped1, was also increased by xanthohumol and showed the capability of relieving cognitive impairment of OVX mice after overexpressed in hippocampus. The 3′ untranslated region of Mpped1 was identified as the target region of miR-532-3p, and agomiR-532-3p remarkably reduced the expression of Mpped1 mRNA.

Conclusions

Xanthohumol has the ability of repairing cognitive impairment through removing the inhibition of miR-532-3p on Mpped1 in mouse hippocampus. This finding not only advances the understanding of neuroprotective mechanism of xanthohumol, but also provides novel treatment targets for dementia of postmenopausal women.

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Data Availability

All data obtained during the current study are available from the corresponding author on reasonable request.

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Funding

This research was supported by the Special Foundation for Talents of Northwest A&F University (Z452017335).

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Authors and Affiliations

  1. Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Xianyang, 712100, China

    Yang Liu, Jiaxing Shao, Ruizhi Qiao, Jiage Li, Chenyu Li & Wei Cao

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  1. Yang Liu
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  2. Jiaxing Shao
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  3. Ruizhi Qiao
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  4. Jiage Li
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  5. Chenyu Li
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  6. Wei Cao
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Contributions

Wei Cao designed the study and wrote the paper; Yang Liu, Jiaxing Shao, Ruizhi Qiao, and Jiage Li provided technical support and obtained data; Yang Liu, Ruizhi Qiao, and Chenyu Li analyzed the data. Yang Liu, Jiaxing Shao, Ruizhi Qiao, and Wei Cao revised the manuscript.

Corresponding author

Correspondence to Wei Cao.

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Ethics approval

All experimental procedures were approved by the Animal Care Commission of the College of Chemistry & Pharmacy, Northwest A&F University. All C57BL/6 J mice used in this study were purchased from the Experimental Animal Center of The Fourth Military Medical University (Xi’an, China). The mice were used for experiments at least 14 days after acclimatization to laboratory conditions and were maintained on a 12/12-h of light/dark cycle and 50–70% humidity with free access to food and water at the Laboratory Animal Facility of the College of Chemistry & Pharmacy, Northwest A&F University.

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Liu, Y., Shao, J., Qiao, R. et al. Xanthohumol improves cognitive impairment by regulating miRNA-532-3p/Mpped1 in ovariectomized mice. Psychopharmacology 240, 1169–1178 (2023). https://doi.org/10.1007/s00213-023-06355-1

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