Ovarian steroids regulate gene expression in the dorsal raphe of old female macaques.
Ovarian steroids regulate gene expression in the dorsal raphe of old female macaques.
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DOI：
10.1016/j.neurobiolaging.2015.10.004
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发表时间：
2016-01
影响因子：
4.2
通讯作者：
Urbanski HF
中科院分区：
文献类型：
--
作者：
Bethea CL;Kohama SG;Reddy AP;Urbanski HF
随着现代人寿命的延长，更年期已成为抑郁、焦虑、认知功能丧失、体重增加、代谢性疾病、骨质疏松症、心血管疾病和神经退行性疾病的重要风险因素。临床研究发现，卵巢类固醇激素治疗(HT)在绝经过渡期间具有有益的神经效应，而且有数据表明这种治疗可以长期持续。为了进一步了解临床研究的分子基础，我们使用qRT-PCR检测了18岁老年恒河猴5-羟色胺能背侧中缝的基因表达，重点关注与抑郁、细胞弹性和神经退行性疾病相关的基因。这些动物被摘除卵巢(OVX，手术绝经)，并接受雌二醇或雌二醇加孕酮羟色胺，或安慰剂，从OVX后2个月开始，持续约4年。在所研究的48个基因中，有36个基因编码支持5-羟色胺神经传递、突触组装、谷氨酸神经传递、DNA修复、伴侣、泛喹酶和运输马达的蛋白质，以及编码可能推迟神经病理发生的蛋白质的基因，观察到显著变化。这些数据揭示了慢性高血压的重要基因靶点，这些基因有助于神经健康。或者，卵巢类固醇的丢失可能会导致基因水平的功能丧失，从而导致绝经后许多可观察到的神经缺陷。
With extended lifespans in modern humans, menopause has become a significant risk factor for depression, anxiety, loss of cognitive functions, weight gain, metabolic disease, osteoporosis, cardiovascular disease and neurodegenerative diseases. Clinical studies have found beneficial neural effects of ovarian steroid hormone therapy (HT) during the menopausal transition and data are emerging that it can be continued long-term. To further understand molecular underpinnings of the clinical studies, we used qRT-PCR to examine gene expression in the serotonergic dorsal raphe of old (>18 yrs) rhesus macaques, focusing on genes related to depression, cellular resilience and neurodegenerative diseases. The animals were ovariectomized (Ovx, surgically menopausal) and subjected to either estradiol or estradiol plus progesterone HT, or to placebo, starting 2 months after Ovx and continuing for ~4 years. Significant changes were observed in 36 out of 48 genes examined that encode proteins supporting serotonin neurotransmission, synapse assembly, glutamate neurotransmission, DNA repair, chaperones, ubiquinases and transport motors, as well as genes encoding proteins that have potential to delay the onset of neuropathologies. The data reveal important gene targets for chronic HT that contribute to neural health. Alternatively, the loss of ovarian steroids may lead to loss of functions at the gene level that contribute to many of the observable neural deficits following menopause.