Effects of oral estrogen, raloxifene and arzoxifene on gene expression in serotonin neurons of macaques
Effects of oral estrogen, raloxifene and arzoxifene on gene expression in serotonin neurons of macaques
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DOI：
10.1016/s0306-4530(01)00054-3
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发表时间：
2002-05-01
影响因子：
3.7
通讯作者：
Michelson, D
中科院分区：
文献类型：
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作者：
Bethea, CL;Mirkes, SJ;Michelson, D
血清素神经系统有助于认知和情感，这两者都表现出性别偏见的病理。我们之前表明，通过硅橡胶植入物对芬塞尔猕猴进行雌激素 (E) 处理会改变色氨酸羟化酶 (TPH)、5-羟色胺再摄取转运蛋白 (SERT) 和 5HT1A 营养受体的基因表达。此外。我们发现猕猴的血清素神经元表达ERβ（ERbeta）。这些研究共同表明，血清素神经系统可以通过 ERbeta 转导雌激素对情绪和认知方面的作用。然而，雌激素替代疗法会增加患乳腺癌和子宫癌的风险。因此，我们质疑选择性雌激素受体调节剂雷洛昔芬和阿佐昔芬是否以类似于 E 的方式对非人灵长类动物模型的血清素神经元中的基因表达产生作用。雌性恒河猴被切除卵巢，并通过吸管瓶每天一次口服赋形剂、雌二醇17β雷洛昔芬或阿佐昔芬，持续30天。然后对动物实施安乐死，并准备中脑用于 TPH、SERT 和 5HT1A 受体 mRNA 的原位杂交，然后进行光密度分析。 E、雷洛昔芬和阿佐昔芬分别使TPH总信号（正像素xOD）显着增加。所有处理的 SERT RNA 光密度均显着下降。 5HT1A 附着受体 mRNA 没有随任何治疗而改变。如果基因表达的这些变化反映在功能蛋白的类似变化上，那么雷洛昔芬或阿佐昔芬可以增加血清素神经传递，而对外周组织几乎没有或没有负面作用。综上所述。选择性雌激素受体调节剂雷洛昔芬和阿佐昔芬。其作用方式类似于天然 E 对血清素神经元中 TPH 和 SERT mRNA 表达的影响。这表明雷洛昔芬和阿佐昔芬是血清素神经元中 ERbeta 的激动剂。然而，与长期植入范例相比，口服给药范例对 E 的反应变化更大，且稳定性较差。 (C) 2002 Elsevier Science Ltd. 保留所有权利。
The serotonin neural system contributes to cognition and affect, both of which exhibit pathologies with gender bias. We previously showed that estrogen (E) treatment of fen sale macaque via Silastic implant alters gene expression for tryptophan hydroxylase (TPH), the serotonin reuptake transporter (SERT) and the 5HT1A nutoreceptor. In addition. we have found that serotonin neurons of macaques express ER beta (ERbeta). Together these studies suggest that the serotonin neural system could transduce the action of estrogen via ERbeta on aspects of mood and cognition. However, estrogen replacement therapy can increase the risk for breast and uterine cancer. Therefore, we questioned whether the selective estrogen receptor modulators, raloxifene and arzoxifene, act in a manner similar to E on gene expression in serotonin neurons of a nonhuman primate model. Female rhesus macaques were ovariectomized and orally dosed with vehicle, estradiol 17beta raloxifene or arzoxifene once per day by sipper bottles for 30 days. The animals were then euthanized and the midbrains were prepared for in situ hybridization for TPH, SERT and 5HT1A receptor mRNAs followed by densitometric analysis. There was a significant increase in TPH total signal (positive pixelsxOD) with E, raloxifene and arzoxifene, respectively. There was a significant decrease in SERT RNA optical density with all treatments. 5HT1A atttoreceptor mRNA did not change with any treatment. If these changes in gene expression are reflected by similar changes in the functional proteins, then raloxifene or arzoxifene could increase serotonin neurotransmission with little or no negative action in peripheral tissues. In conclusion. the selective estrogen receptor modulators, raloxifene and arzoxifene. act in a manner similar to natural E on TPH and SERT mRNA expression in serotonin neurons. This suggests that raloxifene and arzoxifene are agonists at ERbeta in the context of the serotonin neuron. However, the responses to E were more variable and less robust with the oral dosing paradigm compared to a chronic implant paradigm. (C) 2002 Elsevier Science Ltd. All rights reserved.