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Loss of Estrogen Efficacy Against Hippocampus Damage in Long-Term OVX Mice Is Related to the Reduction of Hippocampus Local Estrogen Production and Estrogen Receptor Degradation

Molecular Neurobiology volume 57, pages 3540–3551 (2020)Cite this article

Abstract

Postmenopausal women experience a higher risk for neurodegenerative diseases, including cognitive impairment and ischemic stroke. Many preclinical studies have indicated that estrogen replacement therapy (ERT) may provide protective effects against these neurological diseases. However, the results of Women’s Health Initiative (WHI) studies have led to the proposal of “critical period hypothesis,” which states that there is a precise window of opportunity for administering beneficial hormone therapy following menopause. However, the underlying molecular mechanisms require further characterization. Here, we explored the effects of ERT on cognition decline and global cerebral ischemia (GCI)-induced hippocampal neuronal damage in mice that had experienced both short-term (ovariectomized (OVX) 1 week) and long-term (OVX 10 weeks) estrogen deprivation. We also further explored the concentration of 17β-estradiol (E2) in the circulation and hippocampus and the expression of aromatase and estrogen receptors (ERα, ERα-Ser118, and ERβ). We found that the neuroprotective effectiveness of ERT against hippocampus damage exhibited in OVX1w mice was totally absent in OVX10w mice. Interestingly, the concentration of hippocampal E2 was irreversibly reduced in OVX10w mice, which was related to the decrease of aromatase expression in the hippocampus. In addition, long-term estrogen deprivation (LTED) led to a decrease in estrogen receptor proteins in the hippocampus. Thus, we concluded that the loss of ERT neuroprotection against hippocampus injury in LTED mice was related to the reduction in hippocampus E2 production and estrogen receptor degradation. These results provide several intervention targets to restore the effectiveness of ERT neuroprotection in elderly post-menopausal women.

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Funding Sources

This work was supported by the National Natural Science Foundation of China (no. 81901205, 81801138, 81971226, 81771411), the Beijing Natural Science Foundation (no. 7194321), Beijing Municipal Science and Technology Commission (no. 1811000017180022), Miaopu Foundation of Chinese PLA General Hospital (no. 18KMM47), and Key R&D projects in Shaanxi Province (no. 2017ZDXMSF059).

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  1. Yulong Ma, Min Liu, and Lifang Yang contributed equally to this study.

Affiliations

  1. Anesthesia and Operation Center, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China

    Yulong Ma & Min Liu

  2. Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Air Force Military Medical University, Xi’an, 710032, China

    Yulong Ma & Wugang Hou

  3. Department of Anaesthesiology, The Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, 710003, China

    Lifang Yang & Pei Qin

  4. Department of Burn and Plastic Surgery, The Fourth Medical Center of Chinese PLA General Hospital, Beijing, 100048, China

    Lixia Zhang

  5. Department of Anesthesiology, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, 100700, China

    Hang Guo

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  1. Yulong Ma
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Ma, Y., Liu, M., Yang, L. et al. Loss of Estrogen Efficacy Against Hippocampus Damage in Long-Term OVX Mice Is Related to the Reduction of Hippocampus Local Estrogen Production and Estrogen Receptor Degradation. Mol Neurobiol 57, 3540–3551 (2020). https://doi.org/10.1007/s12035-020-01960-z

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Keywords

  • Estrogen replacement treatment (ERT)
  • Neuroprotection
  • Long-term estrogen deprivation (LTED)
  • Critical period hypothesis
  • Hippocampus-derived estrogen
  • Hippocampus damage