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- Title
CB1 agonism prolongs therapeutic window for hormone replacement in ovariectomized mice.
- 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; Zhang, Kun; Yang, Qi; Yang, Le; Li, Yan-Jiao; Wang, Xin-Shang
- 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.
- Subjects
CANNABINOID receptors; MICE; HORMONE therapy; LONG-term memory; FEAR; SEXUAL desire disorders; RNA metabolism; THERAPEUTICS; BIOCHEMISTRY; RESEARCH; HORMONES; ESTRADIOL; ANIMAL experimentation; RESEARCH methodology; CELL receptors; RNA; EVALUATION research; MEDICAL cooperation; PHENOMENOLOGY; COMPARATIVE studies; OVARIECTOMY; POSTMENOPAUSE
- Publication
Journal of Clinical Investigation, 2019, Vol 129, Issue 6, p2333
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI123689