The Mineralocorticoid Agonist Fludrocortisone Promotes Survival and Proliferation of Adult Hippocampal Progenitors

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.

Adult neurogenesis in the mammalian dentate gyrus

“…Similar effects on glucocorticoid levels also have been produced by stimulation of the hippocampus in humans (Cameron & Glover, ; Rubin, Mandell, & Crandall, ). On the other hand, levels of hippocampal mineralocorticoids acting through mineralocorticoid receptor signalling pathways are associated with neuronal survival in the dentate gyrus, and impaired hippocampal mineralocorticoid receptor signalling has been linked to depression (Gesmundo et al, ). Collectively these data indicate that adult neurogenesis in the hippocampus plays a significant role in stress responses associated with anxiety and depression (Cameron & Glover, ; Jankord & Herman, ).…”

Actions of Brain-Derived Neurotrophic Factor and Glucocorticoid Stress in Neurogenesis

“…On the other hand, mineralocorticoid receptor (MR) to which GCs also bind functions as a positive regulator for neurogenesis. Fludrocortisone, a potent MR agonist, increased the survival and proliferation of rat hippocampal progenitor cells, and these positive effects were attenuated by high dose of dexamethasone [ 50 ], implying that MR has an effect opposite to GR in neurogenesis. Indeed, MR improves deficits in both memory formation and hippocampal neurogenesis caused by chronic early life stress (ELS) [ 51 ].…”

Steroid and Xenobiotic Receptor Signalling in Apoptosis and Autophagy of the Nervous System

“…Recent studies provided evidence that corticosterone-induced injury in rat adrenal pheochromocytoma PC12 cells can be attenuated by HBOB, an HDAC6 inhibitor, by inhibiting mitochondrial GR translocation and the intrinsic apoptosis pathway [ 150 ]. Furthermore, agonizing the MR with fludrocortisone promoted cell survival and proliferation of adult hippocampal progenitors, but inhibited apoptotic signalling, including GSK-3β [ 151 ].…”