10 research outputs found
Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation
Prova tipográfica (In Press)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 ([7a-(acetylthio)-3-oxo-17a-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 ((7a,17a)-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