A Single-Day Treatment with Mifepristone Is Sufficient to Normalize Chronic Glucocorticoid Induced Suppression of Hippocampal Cell Proliferation

Pu Hu, Charlotte Oomen, Anne-Marie van Dam, Jordi Wester, Jiang-Ning Zhou, Marian Joëls, Paul J Lucassen

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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.

Original languageEnglish
JournalPLoS ONE
Issue number9
Publication statusPublished - 2012

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