Brain Specific Estrogen Ameliorates Cognitive Effects of Surgical Menopause in Mice.
Brain Specific Estrogen Ameliorates Cognitive Effects of Surgical Menopause in Mice.
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脑特异性雌激素改善小鼠手术绝经的认知影响。
DOI：
10.1101/2023.08.09.552687
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Stephens,
中科院分区：
文献类型：
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作者：
Salinero,AbigailE;Abi-Ghanem,Charly;Venkataganesh,Harini;Sura,Avi;Smith,RachelM;Thrasher,ChristinaA;Kelly,RichardD;Hatcher,KatherineM;NyBlom,Vanessa;Shamlian,Victoria;Kyaw,Nyi-Rein;Belanger,KaseyM;Gannon,OliviaJ;Stephens,
更年期是一个主要的内分泌变化，导致认知障碍和痴呆风险因素的脆弱性增加。这被认为是由于循环雌激素的丧失，而雌激素在大脑中发挥了许多有效的神经保护作用。绝经后全身性替代雌激素有许多局限性，包括增加雌激素敏感性癌症的风险。因此，一种更有希望的治疗方法可能是仅向大脑输送雌激素，从而限制不良的外周副作用。我们研究了是否可以通过向绝经后小鼠的大脑提供雌激素来提高认知能力。我们通过双侧卵巢切除术（OVX）模拟手术绝经。我们用前体药物10β，17β-二羟基雌二醇-1,4-二烯-3-酮（DHED）治疗小鼠，该药物可以全身给药，但仅在脑内转化为17β-雌二醇。年轻（2.5个月）和中年（11个月）雌性C57BL/6J小鼠接受卵巢切除术和含有载体（胆固醇）或DHED的皮下植入。在3.5个月大（幼龄组）和14.5个月大（中年组）时，小鼠进行了行为测试以评估记忆。ded没有显著改变绝经后中年小鼠的代谢状态。在年轻和中年小鼠中，大脑特异性雌激素ded改善了空间记忆。对中年小鼠的进一步测试也表明，ded改善了工作记忆和识别记忆。这些有希望的结果为未来的研究奠定了基础，这些研究旨在确定这种干预措施在具有合并症风险因素的痴呆模型中是否同样有效。
Menopause is a major endocrinological shift that leads to an increased vulnerability to the risk factors for cognitive impairment and dementia. This is thought to be due to the loss of circulating estrogens, which exert many potent neuroprotective effects in the brain. Systemic replacement of estrogen post-menopause has many limitations, including increased risk for estrogen-sensitive cancers. A more promising therapeutic approach therefore might be to deliver estrogen only to the brain thus limiting adverse peripheral side effects. We examined whether we could enhance cognitive performance by delivering estrogen exclusively to the brain in post-menopausal mice. We modeled surgical menopause via bilateral ovariectomy (OVX). We treated mice with the pro-drug 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), which can be administered systemically but is converted to 17β-estradiol only in the brain. Young (2.5-month) and middle-aged (11-month-old) female C57BL/6J mice received ovariectomy and a subcutaneous implant containing vehicle (cholesterol) or DHED. At 3.5 months old (young group) and 14.5 months old (middle-aged group), mice underwent behavior testing to assess memory. DHED did not significantly alter metabolic status in middle-aged, post-menopausal mice. In both young and middle-aged mice, the brain-specific estrogen DHED improved spatial memory. Additional testing in middle-aged mice also showed that DHED improved working and recognition memory. These promising results lay the foundation for future studies aimed at determining if this intervention is as efficacious in models of dementia that have comorbid risk factors.