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

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.