{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T20:35:35Z","timestamp":1786739735098,"version":"build-2736575974"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","license":[{"start":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>Postmenopausal women with Alzheimer\u2019s disease (AD) exhibit dramatically reduced sensitivity to estrogen replacement therapy, which is though to be related to an estrogen receptor (ER)\u03b1\/ER\u03b2 ratio imbalance arising from a significantly decreased level of ERs of the brain. The aim of our study was to investigate whether valproic acid (VPA) can enhance the beneficial effects of estrogen on cognitive function through restoration of ER\u03b1 and ER\u03b2 expression in the brain. We removed the ovaries of female APP\/PS1 mice to simulate the low estrogen levels present in postmenopausal women and then administered VPA (30 mg\/kg, intraperitoneal injection, once daily), 17\u03b2-estradiol (E2) (2.4 \u03bcg, intraperitoneal injection, once daily), liquiritigenin (LG) (50 \u03bcg\/kg, intragastric infusion, once daily), VPA + E2, or VPA + LG for 4 successive weeks. Compared with treatment with a single drug, treatment with VPA + E2 or VPA + LG significantly increased the level of glycogen synthase kinase 3\u03b2, increased the expression of estrogen receptor \u03b1, reduced the expression of small ubiquitin-like modifiers, and increased the level of estrogen receptor \u03b2. This resulted in enhanced sensitivity to estrogen therapy, reduced amyloid \u03b2 aggregation, reduced abnormal phosphorylation of the tau protein, reduced neuronal loss, increased dendritic spine and postsynaptic density, and significantly alleviated memory loss and learning impairment in mice. This study was approved by the Chongqing Medical University Animal Protection and Ethics Committee, China on March 6, 2013.<\/jats:p>","DOI":"10.4103\/1673-5374.308103","type":"journal-article","created":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T15:09:31Z","timestamp":1613660971000},"page":"2078-2085","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":13,"title":["Combined treatment with valproic acid and estrogen has neuroprotective effects in ovariectomized mice with Alzheimer\u2019s disease"],"prefix":"10.4103","volume":"16","author":[{"given":"Yan-Zhen","family":"Li","sequence":"first","affiliation":[{"name":"Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Jie","family":"Liu","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, 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