Depletion of the neural precursor cell pool by glucocorticoids

Yu, Sheng-Bo; Patchev, Alexandre V.; Wu, Yan; Lu, Jie; Holsboer, Florian; Zhang, Jingzhong; Sousa, Nuno; Almeida, Osborne F. X.

doi:10.1002/ana.21812

Cited by 75 publications

(77 citation statements)

References 44 publications

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“…5 A and B and Fig. S7A) in a GR-dependent manner (i.e., blocked by a simultaneous 24-h treatment with RU-486), in accordance with results obtained in NPCs derived from other brain regions and ages (28,29). In these assays, a 1-h BrdU pulse immediately preceding harvest was used to identify cells progressing through S phase [i.e., BrdU + staining by indirect immunofluorescence (IIF) analysis].…”

Section: Transient Gc Exposure Is Sufficient To Reduce S-phase Progresupporting

confidence: 89%

Nongenomic glucocorticoid receptor action regulates gap junction intercellular communication and neural progenitor cell proliferation

Samarasinghe

Maio

Volonté³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

108

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Glucocorticoids (GCs) are used to treat pregnant women at risk for preterm delivery; however, prenatal exposure to GCs may trigger adverse neurological side effects due to reduced neural progenitor cell (NPC) proliferation. Whereas many established cell-cycle regulators impact NPC proliferation, other signaling molecules, such as the gap junction protein connexin-43 (Cx43), also influence proliferation. Gap junction intercellular communication (GJIC) is influenced by GCs in some cells, but such hormone effects have not been examined in coupled stem cells. We found that both continuous and transient exposure of embryonic day 14.5 mouse neurosphere cultures to dexamethasone (DEX) limits proliferation of coupled NPCs, which is manifested by both a reduction in Sphase progression and enhanced cell-cycle exit. A short (i.e., 1-h) DEX treatment also reduced GJIC as measured by live-cell fluorescence recovery after photobleaching, and altered the synchrony of spontaneous calcium transients in coupled NPCs. GC effects on GJIC in NPCs are transcription-independent and mediated through plasma membrane glucocorticoid receptors (GRs). This nongenomic pathway operates through lipid raft-associated GRs via a site-specific, MAPK-dependent phosphorylation of Cx43, which is linked to GR via caveolin-1 (Cav-1) and c-src. Cav-1 is essential for this nongenomic action of GR, as DEX effects on GJIC, Cx43 phosphorylation, and MAPK activation are not observed in Cav-1 knockout NPCs. As transient pharmacologic inhibition of GJIC triggers reduced S-phase progression but not enhanced cell-cycle exit, the nongenomic GR signaling pathway may operate via distinct downstream effectors to alter the proliferative capacity of NPCs.

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Section: Transient Gc Exposure Is Sufficient To Reduce S-phase Progresupporting

confidence: 89%

Nongenomic glucocorticoid receptor action regulates gap junction intercellular communication and neural progenitor cell proliferation

Samarasinghe

Maio

Volonté³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

108

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“…Moreover, our data are consistent with the results of several investigations that addressed the effect of perinatal glucocorticoid administration on hippocampal neurogenesis in otherwise healthy animals. Neural precursor cells and immature neurons in the hippocampus were shown to be sensitive to the proapoptotic actions of DXM in neonatal rats, leading to significant and sustained reductions in the volume of the dentate gyrus (18). In addition, a one to three day DXM regimen in 4-to 7-day-old rats significantly decreased brain weight, which was associated with a decrease in BrdU-labeled cells in the subpial granular layer (SGL), the subventricular zone (SVZ), and the cortex (16).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to an aggravated hippocampal apoptosis, transcriptome analysis suggests that DXM-induced hippocampal damage in PM may be related to a decrease of proneurogenic processes in the infant rat model (12). Of note, the proapoptotic and antiproliferative properties of DXM on embryonic and neonatal rat hippocampal cells have been previously reported outside of the context of PM (16)(17)(18). The hippocampus is a site of persistent neurogenesis (19), and an increase in the cellular proliferative capacity that might be involved in the regeneration of PM-induced brain damage has been observed in the hippocampi of infant rats (20), adult mice (21), and even patients who died from meningitis (22).…”

mentioning

confidence: 91%

Inhibition of Hippocampal Regeneration by Adjuvant Dexamethasone in Experimental Infant Rat Pneumococcal Meningitis

Bally

Grandgirard

Leib

2016

Antimicrob Agents Chemother

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Pneumococcal meningitis (PM) causes neurological sequelae in up to half of surviving patients. Neuronal damage associated with poor outcome is largely mediated by the inflammatory host response. Dexamethasone (DXM) is used as an adjuvant therapy in adult PM, but its efficacy in the treatment of pneumococcal meningitis in children is controversially discussed. While DXM has previously been shown to enhance hippocampal apoptosis in experimental PM, its impact on hippocampal cell proliferation is not known. This study investigated the impact of DXM on hippocampal proliferation in infant rat PM. Eleven-day-old nursing Wistar rats (n ‫؍‬ 90) were intracisternally infected with Streptococcus pneumoniae to induce experimental meningitis. Treatment with DXM or vehicle was started 18 h after infection, concomitantly with antibiotics (ceftriaxone 100 mg/kg of body weight twice a day [b.i.d.]). Clinical parameters were monitored, and the amount of cells with proliferating activity was assessed using in vivo incorporation of bromodeoxyuridine (BrdU) and an in vitro neurosphere culture system at 3 and 4 d postinfection. DXM significantly worsened weight loss and survival. Density of BrdU-positive cells, as an index of cells with proliferating activity, was significantly lower in DXM-treated animals compared to vehicle controls (P < 0.0001). In parallel, DXM reduced neurosphere formation as an index for stem/progenitor cell density compared to vehicle treatment (P ‫؍‬ 0.01). Our findings provide clear evidence that DXM exerts an antiproliferative effect on the hippocampus in infant rat PM. We conclude that an impairment of regenerative hippocampal capacity should be taken into account when considering adjuvant DXM in the therapeutic regimen for PM in children.

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“…Specifi cally, many recent studies clearly show that glucocorticoids, including synthetic DEX, induce apoptosis of neuronal populations. Yu et al showed that DEX exposure causes apoptosis in immature hippocampal neurons via activation of GR, whereas exposure to RU38486, a GR antagonist, prevents the DEX effect (44) . Additionally, gestational or postnatal exposure to DEX was shown to activate caspase-3, which plays a pivotal role in mechanisms underlying cell death (7) .…”

Section: Glucocorticoids and Cell Deathmentioning

confidence: 99%

The influence of glucocorticoids on neuronal survival and synaptic function

Numakawa¹,

Adachi²,

Richards³

et al. 2012

BioMolecular Concepts

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Glucocorticoids, recognized as stress-related steroid hormones secreted from adrenal glands, have multiple roles in brain function. The concentration of glucocorticoids is regulated by the hypothalamic-pituitary-adrenal axis, and chronically elevated levels of glucocorticoids are putatively involved in the pathophysiology of mental disorders, such as depression. As corticosteroids are also widely used as medical drugs (e.g., for chronic lung disease in infants), the developmental infl uence of glucocorticoids on neuronal survival and synaptic plasticity is a critical concern. Although many reports suggest a biological effect of glucocorticoids on neuronal populations of the central nervous system (CNS), some reports suggest a possibility that glial responses (including regulation of neurotrophic factor expression) to glucocorticoids are different from that of neurons. In the present review, we show an overview of the current knowledge concerning the impact of glucocorticoids on behavior in animal models of depression, and on cell survival and function in the CNS.

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Depletion of the neural precursor cell pool by glucocorticoids

Cited by 75 publications

References 44 publications

Nongenomic glucocorticoid receptor action regulates gap junction intercellular communication and neural progenitor cell proliferation

Nongenomic glucocorticoid receptor action regulates gap junction intercellular communication and neural progenitor cell proliferation

Inhibition of Hippocampal Regeneration by Adjuvant Dexamethasone in Experimental Infant Rat Pneumococcal Meningitis

The influence of glucocorticoids on neuronal survival and synaptic function

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