CB1 agonism prolongs therapeutic window for hormone replacement in ovariectomized mice

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 17[beta]-estradiol (E2) was normal in mice 1 week after ovariectomy ([OVX.sub.ST]), but it was impaired in mice 3 months after ovariectomy ([OVX.sub.LT]). 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 [OVX.sub.LT] 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 [OVX.sub.LT] 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.
Introduction Natural menopause is a gradual process that occurs for most women between the ages of 47 and 55 (1). Although hormone therapy (HT) is used as an effective treatment [...]