Department of Pharmacy, Precision Pharmacy and Drug Development Center, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi, China.
J Clin Invest. 2019 May 6;129(6):2333-2350. doi: 10.1172/JCI123689.
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.
激素疗法（HT）据近期临床研究报道，对改善老年绝经后女性的学习和记忆能力效果不佳；然而，失败的原因尚不清楚。有人提出雌激素治疗的“机会之窗”来解释这种不足。在这里，我们发现，17β-雌二醇（E2）对切除卵巢 1 周后的小鼠的记忆消退和长期抑郁的促进作用正常，但对切除卵巢 3 个月后的小鼠的作用受损。高通量测序显示，miR-221-5p 的减少，通过上调 Neurl1a/b 促进大麻素受体 1（CB1）泛素化，这在 E2 处理的 OVXLT 小鼠中发生。与 46-55 岁围绝经期女性的样本相比，来自 56-65 岁绝经后女性的血液样本中 miR-221-5p 和 2-花生四烯酸甘油的含量降低。补充 miR-221-5p 或用 CB1 激动剂治疗可挽救 E2 处理的 OVXLT 小鼠的恐惧消退损伤。本研究表明，通过与 CB1 激动剂共同治疗，可延长小鼠 HT 的时间窗口，这暗示了 HT 在长期绝经后女性中的潜在策略。
