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

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 ([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. Molecular Psychiatry (2005) 10, 790-798.

Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex

“…Despite the observations showing glucocorticoid neuroendangerment in the hippocampus, and DEX dependent decreases in cortical neuron numbers (Crochemore et al, 2005, Kreider et al, 2006, to the best of our knowledge, glucocorticoid endangerment of cortical neuron responses to a secondary metabolic insult, have not yet been described. The results of our studies have established that activated GR increases Bnip3 transcription in the anterior and posterior cingulate cortices of the postnatal female rat, but not in the male cingulate cortex.…”

“…However, increases in primary cortical neuron death were measured following overexpression of Bnip3 protein, independent of glucocorticoid and hypoxia treatment. Previous studies have established that glucocorticoids can endanger the CNS by increasing levels of the pro-apoptotic protein Bax and decreasing levels of the anti-apoptotic proteins Bcl-2 and Bcl-X L , in the juvenile and adult rat hippocampus (Almeida et al, 2000) and in primary hippocampal neurons (Crochemore et al, 2005). Furthermore, DEX treatment results in an increase in apoptosis in the adult rat hippocampus and striatum (Hassan et al, 1996, Haynes et al, 2001.…”

“…A possible explanation may be due to the presence of low corticosterone levels in our culture system, which activates the MR. In primary rat hippocampal neurons, activated MR circumvents GR induced hippocampal neuron death (Crochemore et al, 2005). Furthermore, Crochemore et al, (2005) suggest that in culture, nanomolar concentrations of corticosterone are sufficient to inhibit GR's killing activities.…”

“…Furthermore, Bnip3 interactions with other proteins are mediated by the TM domain and not the BH3 domain (Chen et al, 1997, Ray et al, 2000, the site within BH3-only proteins that are implicated as essential to Bax activation (Wei et al, 2001). Regardless, the putative interaction of Bnip3 and Bax has not been reported in the current literature.Despite the observations showing glucocorticoid neuroendangerment in the hippocampus, and DEX dependent decreases in cortical neuron numbers (Crochemore et al, 2005, Kreider et al, 2006, to the best of our knowledge, glucocorticoid endangerment of cortical neuron responses to a secondary metabolic insult, have not yet been described. The results of our studies have established that activated GR increases Bnip3 transcription in the anterior and posterior cingulate cortices of the postnatal female rat, but not in the male cingulate cortex.…”

Glucocorticoids and circadian clock control of cell proliferation: At the interface between three dynamic systems

“…Interestingly, in intact animals, glucocorticoid receptor agonists can induce apoptosis in granule cells, and mineralocorticoid receptor activation can protect against this effect [141,142]. It thus appears that a balance between MR and GR activation, affecting both cell proliferation and survival, is required for normal neurogenesis in the dentate gyrus.…”