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CB1 agonism prolongs therapeutic window for hormone replacement in ovariectomized mice
Kun Zhang, … , Shui-bing Liu, Ming-gao Zhao
Kun Zhang, … , Shui-bing Liu, Ming-gao Zhao
Published May 6, 2019
Citation Information: J Clin Invest. 2019;129(6):2333-2350. https://doi.org/10.1172/JCI123689.
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Research Article Endocrinology Neuroscience

CB1 agonism prolongs therapeutic window for hormone replacement in ovariectomized mice

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Abstract

Hormone therapy (HT) is reported to be deficient in improving learning and memory in older postmenopausal women according to recent clinical studies; however, the reason for failure is unknown. A “window of opportunity” for estrogen treatment is proposed to explain this deficiency. Here, we found that facilitation of memory extinction and long-term depression by 17β-estradiol (E2) was normal in mice 1 week after ovariectomy (OVXST), but it was impaired in mice 3 months after ovariectomy (OVXLT). High-throughput sequencing revealed a decrease of miR-221-5p, which promoted cannabinoid receptor 1 (CB1) ubiquitination by upregulation of Neurl1a/b in E2-treated OVXLT mice. Blood samples from postmenopausal women aged 56–65 indicated decreases of miR-221-5p and 2-arachidonoylglycerol compared with samples from perimenopausal women aged 46–55. Replenishing of miR-221-5p or treatment with a CB1 agonist rescued the impairment of fear extinction in E2-treated OVXLT mice. The present study demonstrates that an HT time window in mice can be prolonged by cotreatment with a CB1 agonist, implying a potential strategy for HT in long-term menopausal women.

Authors

Kun Zhang, Qi Yang, Le Yang, Yan-jiao Li, Xin-shang Wang, Yu-jiao Li, Rui-li Dang, Shao-yu Guan, Yan-yan Guo, Ting Sun, Yu-mei Wu, An Liu, Yan Zhang, Shui-bing Liu, Ming-gao Zhao

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Figure 5

miR-221-5p responsible for impairment of fear extinction.

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miR-221-5p responsible for impairment of fear extinction.
(A) Sample ima...
(A) Sample images showing miR-221-5p agomir–Cy3 (red) and miR-541-3p agomir–Cy3 (red) injection and nucleus (DAPI, blue) in prefrontal cortex. (B) miR-221-5p agomir but not miR-541-3p agomir rescued memory extinction in E2-treated OVXLT mice. n = 8 mice per group. **P < 0.01 vs. scramble by univariate ANOVA after lower-bound correction as repeated-measurement data. (C) miR-221-5p agomir rescued impairment of LTD induced by E2 in OVXLT mice. Arrow indicates the point of LFS application. n = 8 slices from 4 mice. **P < 0.01 by unpaired Student’s t test. (D) Increase of CB1 by miR-221-5p mPFC injection in E2-treated OVXLT mice. n = 5 mice per group. **P < 0.01 between the marked groups by 2-way ANOVA followed by Bonferroni’s post hoc test. (E) Combining miR-221-5p agomir with E2 + ACEA did not further increase memory extinction as compared with miR-221-5p + ACEA in OVXLT mice. n = 8 mice per group. **P < 0.01 between the marked groups by univariate ANOVA after lower-bound correction as repeated-measurement data. (F) mPFC injection of miR-221-5p antagomir impaired fear memory extinction in E2-treated OVXST mice, similarly to what was seen in E2-treated OVXLT mice. n = 8 mice per group. **P < 0.01 vs. scramble by univariate ANOVA after lower-bound correction as repeated-measurement data. Experimenters were blinded to the treatment except in C. Data are represented as mean ± SEM.

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