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

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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 2005

Fingerprint

Mineralocorticoid Receptors
Mineralocorticoids
Dexamethasone
Glucocorticoids
Apoptosis
Neurons
Potassium
Cell Death
Mineralocorticoid Receptor Antagonists
Spironolactone
Microtubule-Associated Proteins
Glucocorticoid Receptors
Masks
Corticosterone
Carboxylic Acids
Aldosterone
Culture Media
Hippocampus
Salts

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health

Cite this

Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation. / Crochemore, C.; Lu, J.; Wu, Y.; Liposits, Z.; Sousa, N.; Holsboer, F.; Almeida, O. F X.

In: Molecular Psychiatry, Vol. 10, No. 8, 08.2005, p. 790-798.

Research output: Contribution to journalArticle

Crochemore, C. ; Lu, J. ; Wu, Y. ; Liposits, Z. ; Sousa, N. ; Holsboer, F. ; Almeida, O. F X. / Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation. In: Molecular Psychiatry. 2005 ; Vol. 10, No. 8. pp. 790-798.
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