A single-day treatment with mifepristone is sufficient to normalize chronic glucocorticoid induced suppression of hippocampal cell proliferation.
A single-day treatment with mifepristone is sufficient to normalize chronic glucocorticoid induced suppression of hippocampal cell proliferation.
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单日米非司酮治疗足以使慢性糖皮质激素引起的海马细胞增殖抑制正常化
DOI：
10.1371/journal.pone.0046224
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lucassen PJ
中科院分区：
文献类型：
--
作者：
Hu P;Oomen C;van Dam AM;Wester J;Zhou JN;Joëls M;Lucassen PJ
背景慢性应激或长期给予糖皮质激素抑制成年大鼠齿状回新生细胞的增殖和/或存活。早些时候，我们发现在21天皮质酮治疗的最后4天给予糖皮质激素受体拮抗剂米非司酮完全使新生细胞数量正常化。在这里，我们的目的是更好地了解米非司酮如何达到这种效果，并质疑是否更短（一天）米非司酮治疗（而不是4天）也足以使神经发生正常化。方法我们使用免疫组织化学标记物BrdU，doublecortin，增殖细胞核抗原以及胶质细胞酸性蛋白，在皮质酮（与溶剂）治疗17或21天后，研究神经发生过程的各个步骤。结果皮质酮主要抑制神经元细胞的增殖，米非司酮可完全逆转皮质酮的抑制作用。令人惊讶的是，皮质类固醇对神经发生的作用甚至可以通过米非司酮的单日治疗（第18天）完全重置，尽管在随后的日子里持续暴露于皮质酮。结论我们的研究结果强调，新的抗抑郁药的治疗效果的研究，特别是那些针对HPA活性或糖皮质激素受体，应探讨减少治疗时间的可能性。
Background Chronic stress or prolonged administration of glucocorticoids suppresses proliferation and/or survival of newborn cells in adult rat dentate gyrus. Earlier we showed that administration of the glucocorticoid receptor antagonist mifepristone during the final 4 days of a 21 days period of corticosterone treatment fully normalized the number of newborn cells. Here we aimed to better understand how mifepristone achieves this effect and questioned whether an even shorter (single day) mifepristone treatment (instead of 4 days) also suffices to normalize neurogenesis. Methods We investigated various steps of the neurogenic process, using the immunohistochemical markers BrdU, doublecortin, proliferating cell nuclear antigen as well as glial fibrillary acidic protein, after 17 or 21 days of corticosterone (versus vehicle) treatment. Results Corticosterone primarily attenuates the proliferation of cells which subsequently develop into neurons; this is fully reversed by mifepristone. Surprisingly, the corticosteroid effects on neurogenesis can even be fully re-set by a single-day treatment with mifepristone (on day 18), despite the continued corticosterone exposure on subsequent days. Conclusions Our results emphasize that studies into the therapeutical efficacy of new antidepressants, especially those targeting HPA-activity or the glucocorticoid receptor, should explore the possibility to reduce treatment duration.
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