CB1 agonism prolongs therapeutic window for hormone replacement in ovariectomized mice.
CB1 agonism prolongs therapeutic window for hormone replacement in ovariectomized mice.
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DOI：
10.1172/jci123689
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发表时间：
2019-05
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通讯作者：
Kun Zhang;Qi Yang;Le Yang;Yan-jiao Li;Xin-shang Wang;Yu-jiao Li;Rui Dang;Shao-yu Guan;Yan-Yan Guo-Yan;Ting Sun;Yu-Mei Wu;An Liu;Yan Zhang;Shui-bing Liu;Ming-gao Zhao
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作者：
Kun Zhang;Qi Yang;Le Yang;Yan-jiao Li;Xin-shang Wang;Yu-jiao Li;Rui Dang;Shao-yu Guan;Yan-Yan Guo-Yan;Ting Sun;Yu-Mei Wu;An Liu;Yan Zhang;Shui-bing Liu;Ming-gao Zhao
根据最近的临床研究，激素疗法(HT)在改善绝经后老年妇女的学习和记忆方面存在缺陷；然而，失败的原因尚不清楚。一个雌激素治疗的“机会之窗”被提出来解释这一缺陷。在此，我们发现17-雌二醇(17β-estadiol，E_2)促进小鼠去卵巢后1周的记忆消退和长期抑郁是正常的，而在去卵巢后3个月的小鼠则受到损害。高通量测序显示，在E2处理的OVXLT小鼠中，miR-221-5p的表达减少，这通过上调Neurl1a/b促进了大麻样受体1(CB1)的泛素化。56-65岁的绝经后妇女的血液样本显示，与46-55岁的围绝经期妇女的样本相比，miR-221-5P和2-花生四烯酸甘油的水平降低。补充miR-221-5p或用CB1激动剂治疗可以挽救E2治疗的OVXLT小鼠恐惧消退的损害。目前的研究表明，与CB1激动剂联合治疗可以延长小鼠的高血压时间窗口，这意味着在长期绝经妇女中治疗高血压的一种潜在策略。
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.