Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation

C. Crochemore, J. Lu, Y. Wu, Z. Liposits, N. Sousa, F. Holsboer, O. F.X. Almeida

Research output: Contribution to journalArticle

147 Citations (Scopus)

Abstract

An important question arising from previous observations in vivo is whether glucocorticoids can directly influence neuronal survival in the hippocampus. To this end, a primary postnatal hippocampal culture system containing mature neurons and expressing both glucocorticoid (GR) and mineralocorticoid (MR) receptors was developed. Results show that the GR agonist dexamethasone (DEX) targets neurons (microtubule-associated protein 2-positive cells) for death through apoptosis. GR-mediated cell death was counteracted by the MR agonist aldosterone (ALDO). Antagonism of MR with spironolactone ([7α-(acetylthio) -3-oxo-17α-pregn-4-ene-21 carbolactone] (SPIRO)) causes a dose-dependent increase in neuronal apoptosis in the absence of DEX, indicating that nanomolar levels of corticosterone present in the culture medium, which are sufficient to activate MR, can mask the apoptotic response to DEX. Indeed, both SPIRO and another MR antagonist, oxprenoate potassium ((7α,17α)-17-hydroxy-3- oxo-7-propylpregn-4-ene-21-carboxylic acid, potassium salt (RU28318)), accentuated DEX-induced apoptosis. These results demonstrate that GRs can act directly to induce hippocampal neuronal death and that demonstration of their full apoptotic potency depends on abolition of survival-promoting actions mediated by MR.

Original languageEnglish
Pages (from-to)790-798
Number of pages9
JournalMolecular Psychiatry
Volume10
Issue number8
DOIs
Publication statusPublished - Aug 1 2005

Keywords

  • Apoptosis
  • Dexamethasone
  • Glucocorticoid receptor
  • Hippocampus
  • Mineralocorticoid receptor
  • RU28318
  • Spironolactone

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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