Institute of Anatomy I, Cellular Neurobiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Endocrinology. 2010 Mar;151(3):1153-60. doi: 10.1210/en.2009-0254. Epub 2010 Jan 22.
Recently, inhibition of estrogen synthesis by aromatase inhibitors has become a favored therapy for breast cancer in postmenopausal women. Estrogen is, however, important for synapse formation in the hippocampus. Inhibition of aromatase induces spine synapse loss in organotypic hippocampal slice cultures. We therefore studied the effect of systemic treatment with the potent aromatase inhibitor letrozole on spine synapse formation and synaptic proteins in the hippocampi of female mice for periods of 7 d and 4 wk. In cyclic, letrozole-treated females and in ovariectomized, letrozole-treated females, the number of spine synapses was significantly reduced in the hippocampus but not in the prefrontal or cerebellar cortex. Consequently, the expression of the N-methyl-D-aspartate receptor NR1 was significantly down-regulated after treatment with letrozole. In cyclic animals the expression of the synaptic proteins synaptophysin and spinophilin was down-regulated in response to letrozole. In ovariectomized animals, however, protein expression was down-regulated after 7 d of treatment, whereas the expression was up-regulated after 4 wk of treatment. Our results indicate that systemic inhibition of aromatase in mice affects structural synaptic plasticity in the hippocampus. This may contribute to cognitive deficits in postmenopausal women treated with aromatase inhibitors.
最近，通过芳香化酶抑制剂抑制雌激素合成已成为绝经后妇女乳腺癌的首选治疗方法。然而，雌激素对于海马体中的突触形成很重要。芳香化酶抑制剂的抑制会诱导器官型海马切片培养物中的棘突突触丧失。因此，我们研究了全身性应用强效芳香化酶抑制剂来曲唑治疗 7 天和 4 周对雌性小鼠海马体中棘突突触形成和突触蛋白的影响。在周期性、来曲唑治疗的雌性动物和卵巢切除、来曲唑治疗的雌性动物中，海马体中的棘突突触数量明显减少，但在额前皮质或小脑皮质中没有减少。因此，来曲唑治疗后 N-甲基-D-天冬氨酸受体 NR1 的表达明显下调。在周期性动物中，来曲唑处理会导致突触蛋白突触小泡蛋白和棘突蛋白的表达下调。然而，在卵巢切除动物中，治疗 7 天后蛋白表达下调，而治疗 4 周后蛋白表达上调。我们的结果表明，在小鼠中系统性抑制芳香化酶会影响海马体中的结构突触可塑性。这可能导致接受芳香化酶抑制剂治疗的绝经后妇女出现认知缺陷。
