Progesterone reverses the spatial memory enhancements initiated by tonic and cyclic oestrogen therapy in middle-aged ovariectomized female rats
Progesterone reverses the spatial memory enhancements initiated by tonic and cyclic oestrogen therapy in middle-aged ovariectomized female rats
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DOI：
10.1111/j.1460-9568.2006.04867.x
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发表时间：
2006-07-01
影响因子：
3.4
通讯作者：
Granholm, Ann-Charlotte
中科院分区：
文献类型：
--
作者：
Bimonte-Nelson, Heather A.;Francis, Kevin R.;Granholm, Ann-Charlotte
虽然一些研究表明卵巢激素疗法 (HT) 有益于记忆力并降低更年期女性患阿尔茨海默氏病的风险，但一些最新的研究表明，这种疗法无效或有害。尽管存在无效和负面的认知发现，但大量研究显示出积极的效果，这引出了一个问题：哪些因素决定了HT是否充当神经保护剂或大脑功能的危险因素。使用中年雌性大鼠，我们直接比较了六种 HT。我们评估了卵巢切除术、低剂量补药、高剂量补药和每两周一次的周期雌二醇治疗的效果，以及黄体酮是否改变了这些雌激素疗法中任何一种的有效性。使用莫里斯迷宫的变体对动物进行空间和复杂提示（迷宫内模式）参考记忆的测试。补品低剂量和循环雌二醇治疗改善了空间表现，而添加黄体酮则逆转了雌二醇的这些有益的认知作用。此外，所有小组都学会了在提示任务上定位平台；然而，以自我为中心的循环策略与假卵巢完整组和激素替代组一起使用，显示出最有效的搜索策略。尽管第一次认知评估后 8 周的记忆保留问题得到了解决，但在第一次和第二次测试之间大量动物死亡，使得重新测试无法解释许多组间比较。具体来说，在为期 17 周的实验中，两种剂量的强效雌二醇均显着增加了死亡人数，而循环雌二醇治疗则没有。黄体酮减少了因补强雌二醇治疗而导致的死亡人数。我们的研究结果表明，雌二醇替代剂量以及孕酮的存在会影响雌二醇治疗的认知结果。此外，HT 对认知的影响与死亡率之间似乎并不相关。
While some research has indicated that ovarian hormone therapy (HT) benefits memory and decreases risk of Alzheimer's disease in menopausal women, several newer studies have shown null or detrimental effects. Despite the null and negative cognitive findings, the numerous studies showing positive effects beg the question of what factors determine whether HT acts as a neuroprotectant or a risk factor for brain functioning. Using middle-aged female rats, we directly compared six HTs. We evaluated the effects of ovariectomy, tonic low-dose, tonic high-dose and biweekly cyclic estradiol treatment, as well as whether progesterone altered the effectiveness of any one of these oestrogen regimens. Animals were tested on spatial and complex cued (intramaze patterns) reference memory using variants of the Morris maze. The tonic low-dose and cyclic estradiol treatments improved spatial performance, while the addition of progesterone reversed these beneficial cognitive effects of estradiol. Additionally, all groups learned to locate the platform on the cued task; however, an egocentric circling strategy was used with sham ovary-intact and hormone-replacement groups showing the most efficient search strategy. Although the question of memory retention 8 weeks after the first cognitive assessment was addressed, a large number of animals died between the first and second test, rendering the retest uninterpretable for many group comparisons. Specifically, both doses of tonic estradiol dramatically increased the number of deaths during the 17-week experiment, while the cyclic estradiol treatment did not. Progesterone decreased the number of deaths due to tonic estradiol treatment. Our findings suggest that the dose of estradiol replacement as well as the presence of progesterone influences the cognitive outcome of estradiol treatment. Further, there appears to be a dissociation between HT effects on cognition and mortality rates.