Supraphysiologic doses of 17β-estradiol aggravate depression-like behaviors in ovariectomized mice possibly via regulating microglial responses and brain glycerophospholipid metabolism

Journal of Neuroinflammation

Research

Shuang Liu¹  Wendi Chen¹  Yunna Ning¹  Jing Zhang¹  Yueran Zhao¹  Ming Li¹  Yongzhi Cao¹  Xin Liu¹ 

[1] Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China;Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China;National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, 250012, Jinan, Shandong, China;

关键词: 17β-Estradiol;    Estrogen replacement therapy;    Menopausal syndrome;    Depression;    Microglial;    Glycerophospholipid metabolism;   

DOI  :  10.1186/s12974-023-02889-5

 received in 2023-04-29, accepted in 2023-08-31,  发布年份 2023

来源: Springer

【 摘 要 】

Background17β-Estradiol (E2) is generally considered neuroprotective in humans. However, the current clinical use of estrogen replacement therapy (ERT) is based on the physiological dose of E2 to treat menopausal syndrome and has limited therapeutic efficacy. The efficacy and potential toxicity of superphysiological doses of ERT for menopausal neurodegeneration are unknown.MethodsIn this study, we investigated the effect of E2 with a supraphysiologic dose (0.5 mg/kg, sE2) on the treatment of menopausal mouse models established by ovariectomy. We performed the open field, Y-maze spontaneous alternation, forced swim tests, and sucrose preference test to investigate behavioral alterations. Subsequently, the status of microglia and neurons was detected by immunohistochemistry, HE staining, and Nissl staining, respectively. Real-time PCR was used to detect neuroinflammatory cytokines in the hippocampus and cerebral cortex. Using mass spectrometry proteomics platform and LC–MS/ MS-based metabolomics platform, proteins and metabolites in brain tissues were extracted and analyzed. BV2 and HT22 cell lines and primary neurons and microglia were used to explore the underlying molecular mechanisms in vitro.ResultssE2 aggravated depression-like behavior in ovariectomized mice, caused microglia response, and increased proinflammatory cytokines in the cerebral cortex and hippocampus, as well as neuronal damage and glycerophospholipid metabolism imbalance. Subsequently, we demonstrated that sE2 induced the pro-inflammatory phenotype of microglia through ERα/NF-κB signaling pathway and downregulated the expression of cannabinoid receptor 1 in neuronal cells, which were important in the pathogenesis of depression.ConclusionThese data suggest that sE2 may be nonhelpful or even detrimental to menopause-related depression, at least partly, by regulating microglial responses and glycerophospholipid metabolism.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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