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 3

Decreased CB1 in mPFC and rescue of impairment of memory extinction by activation of CB1 in E2-treated OVXLT mice.

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Decreased CB1 in mPFC and rescue of impairment of memory extinction by a...
(A) Levels of CB1 in mPFCs of mice after OVX. n = 6 mice per group; 1-way ANOVA followed by Bonferroni’s post hoc test; *P < 0.05 and **P < 0.01 vs. sham group, ##P < 0.01 vs. mice 1 week after OVX. (B) Synaptic fEPSP response to ACEA (CB1 agonist, 1 μM) perfusion in mPFC slices from different mice. Inset shows the averaged fEPSP slope from 90 to 120 minutes. n = 8 slices from 4 mice per group. **P < 0.01 between the marked groups by 1-way ANOVA followed by Bonferroni’s post hoc test. (C) Effects of ACEA (0.5 mg/kg, s.c.) combined with E2 (0.1 mg/kg, s.c.) on fear memory formation and extinction. (D) Effects of JZL184 (2-AG hydrolysis enzyme inhibitor, 8 mg/kg, s.c.) or WIN55,212-2 (nonselective cannabinoid receptor agonist, 1 mg/kg, s.c.) combined with E2 on fear memory formation and extinction, and blockage of AM251 (CB1-specific antagonist, 3 mg/kg, s.c.). (C and D) n = 8 mice per group. **P < 0.01 vs. sham or OVXLT mice by univariate ANOVA after lower-bound correction as repeated-measurement data. (E) Images showing AAV-CMV-mCherry-Cnr1 injection in mPFC of OVXLT mice. (F) Inhibitory avoidance test was carried out 4 weeks after AAV injection. n = 8 mice per group. **P < 0.01 vs. mCherry by univariate ANOVA after lower-bound correction as repeated-measurement data. (G) Representative images of basilar dendrites from mPFC neurons. Number of total and different spine subtypes. n = 60 neurons from 6 mice per group. **P < 0.01 between the marked groups by 2-way ANOVA followed by Bonferroni’s post hoc test. Experimenters were blinded to the treatment. Data are represented as mean ± SEM.