Abstract
Glucocorticoid receptor (GR) activation has been shown to reduce adult hippocampal progenitor cell proliferation and neurogenesis. By contrast, mineralocorticoid receptor (MR) signaling is associated with neuronal survival in the dentate gyrus of the hippocampus, and impairment of hippocampal MR has been linked to pathological conditions, such as depression or neurodegenerative disorders. Here, we aimed to further clarify the protective role of MR in adult hippocampal neurons by studying the survival and proliferative effects of the highly potent MR agonist fludrocortisone (Fludro) in adult rat hippocampal progenitor cells (AHPs), along with the associated signaling mechanisms. Fludro, which upregulated MR but not GR expression, increased survival and proliferation and prevented apoptosis in AHPs cultured in growth factor-deprived medium. These effects were blunted by the MR antagonist spironolactone and by high doses of the GR agonist dexamethasone. Moreover, they involved signaling through cAMP/protein kinase A (PKA)/cAMP response element-binding protein, phosphoinositide 3-kinase (PI3K)/Akt and its downstream targets glycogen synthase kinase-3β (GSK-3β) and mammalian target of rapamycin. Furthermore, Fludro attenuated the detrimental effects of amyloid-β peptide 1–42 (Aβ1–42) on cell survival, proliferation, and apoptosis in AHPs, and increased the phosphorylation of both PI3K/Akt and GSK-3β, which was reduced by Aβ1–42. Finally, Fludro blocked Aβ1–42-induced hyperphosphorylation of Tau protein, which is a main feature of Alzheimer’s disease. Overall, these results are the first to show the protective and proliferative role of Fludro in AHPs, suggesting the potential therapeutic importance of targeting MR for increasing hippocampal neurogenesis and for treating neurodegenerative diseases.
Highlights
The hypothalamic–pituitary–adrenal (HPA) axis is the endocrine center of the stress system, consisting of corticotrophin-releasing hormone (CRH), pituitary adrenocorticotropic hormone (ACTH), and adrenal corticosteroid release
Real-time polymerase chain reaction (PCR) analysis showed that treatment with Fludro (1 μM) for 24 h strongly increased mineralocorticoid receptors (MRs) gene expression in adult rat hippocampal progenitor cells (AHP) (Figure 1B), whereas no variation was observed for glucocorticoid receptors (GRs) (Figure 1C)
Once ascertained MR and GR expression, we sought to determine the biological effects induced by different concentrations (0.01–2 μM) of the potent synthetic MR agonist Fludro in AHPs, which were cultured in growth factor-deprived medium
Summary
The hypothalamic–pituitary–adrenal (HPA) axis is the endocrine center of the stress system, consisting of corticotrophin-releasing hormone (CRH), pituitary adrenocorticotropic hormone (ACTH), and adrenal corticosteroid release. Corticosteroids influence neuronal plasticity and excitability, neurogenesis and neuronal death, as well as neuroendocrine control and behavioral responses [1]. Their actions in the brain are mediated by glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs), which act in the cell nuclei as activators of gene transcription factors. Due to the differences in affinity, MR is always occupied by corticosterone, even at basal levels of HPA axis activity; higher hormone levels, after stress or circadian peak, progressively saturate the GR [3]. Rapid non-genomic effects have been demonstrated for MR and GR, which act as low-affinity membrane-associated receptor variants in response to rising corticosteroid levels [4]
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