Dexamethasone inhibits proliferation of adult hippocampal neurogenesis in vivo and in vitro

Kim, Jong Bin; Ju, Jae Yeol; Kim, Ju Hee; Kim, Think‐You; Yang, Byung-Hwan; Lee, Yong-Sung; Son, Hyeon

doi:10.1016/j.brainres.2004.07.093

Cited by 131 publications

(82 citation statements)

References 29 publications

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“…It is possible that the repeated injection procedure is stressful to the animals, which could cause suppression of cell proliferation. In support of this, stress hormones and stress have been demonstrated to decrease cell proliferation in the dentate gyrus (41)(42)(43)(44).…”

Section: Discussionmentioning

confidence: 78%

Leptin Increases Adult Hippocampal Neurogenesis in Vivo and in Vitro

Garza

Guo

Zhang

et al. 2008

Journal of Biological Chemistry

212

161

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Leptin, an adipose-derived hormone, has been implicated in several physiological processes involving the hippocampus. However, the role of leptin in adult hippocampal neurogenesis remains unknown. Here we show that leptin regulates neurogenesis in the dentate gyrus of adult mice as well as in cultured adult hippocampal progenitor cells. Chronic administration of leptin to adult mice increased cell proliferation without significant effects on the differentiation and the survival of newly proliferated cells in the dentate gyrus. The expression of the long form leptin receptor, LepRb, was detected in hippocampal progenitor cells by reverse transcription-PCR and immunohistochemistry. Leptin treatment also increased proliferation of cultured adult hippocampal progenitor cells. Analysis of signal transduction pathways revealed that leptin stimulated phosphorylation of Akt and STAT3 but not ERK1/2. Furthermore, pretreating the cells with specific inhibitors of Akt or STAT3 attenuated leptin-induced cell proliferation in a dose-dependent manner. Taken together, our results support a role for leptin in adult hippocampal neurogenesis and suggest the involvement of the Akt and STAT3 signaling pathways in mediating the actions of leptin on neurogenesis.The dentate gyrus of the hippocampus is one of the two brain regions where adult neurogenesis persists throughout life. Adult neurogenesis is regulated by physiological and pathological events and modulated by pharmacological manipulations at any of three primary stages: cell proliferation, differentiation, and survival. Neurogenesis in the dentate gyrus has been found to be negatively influenced by stress and is suppressed in various animal models of depression (1-3). Conversely, new neuron generation in the dentate gyrus is stimulated by treatment with antidepressants (4, 5). Also, neurotrophins, growth factors, and cytokines have been shown to be capable of modulating neurogenesis of the adult dentate gyrus (6 -8).Leptin is an adipocyte-derived cytokine encoded by the obese (ob) gene. It circulates as a 16-kDa peptide and is transported into the brain via a saturable transport system (9 -11). Leptin signals in the brain by binding to the long form leptin receptor (LepRb), 2 a Type I cytokine receptor, which results in Janus kinase 2 (Jak2)-mediated phosphorylation of two tyrosine residues (Tyr 985 and Tyr 1138 ) in the cytoplasmic tail of the receptor (12). Phosphorylated Tyr 985 of LepRb recruits SH2-containing protein-tyrosine phosphatase-2, leading to activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) pathway (13,14). Phosphorylated Tyr 1138 of LepRb activates signal transducer and activator of transcription 3 (STAT3), which dimerizes and is translocated to the nucleus where it acts as a transcription factor (12). Jak2 also phosphorylates insulin receptor substrate-1 and -2, resulting in activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway (15, 16).Leptin is well known for its role in the control of food intake a...

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Section: Discussionmentioning

confidence: 78%

Leptin Increases Adult Hippocampal Neurogenesis in Vivo and in Vitro

Garza

Guo

Zhang

et al. 2008

Journal of Biological Chemistry

212

161

View full text Add to dashboard Cite

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“…So, it is necessary for the investigations of the positive effects of drugs and/or factors on ADP proliferation to decrease it. Second, it has been shown that glucocorticoids are the physiological negative regulator of neurogenesis in the adult DG [30,31] and DEX is a specific agonist of glucocorticoid receptor. GDNF had no significant effect on the number of cells at any dose in the presence (One-way ANOVA and Dunnett's post hoc test, F(3, 28)=0.885, p=0.4608, Fig.1A) or the absence (data not shown) of 5 µM DEX.…”

Section: Gdnf Has No Effect On Adp Proliferation and Apoptosismentioning

confidence: 99%

GDNF facilitates differentiation of the adult dentate gyrus-derived neural precursor cells into astrocytes via STAT3

Boku

Nakagawa

Takamura

et al. 2013

Biochemical and Biophysical Research Communications

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While the pro-neurogenic actions of antidepressants in the adult hippocampal dentate gyrus (DG) are thought to be one of the mechanisms through which antidepressants exert their therapeutic actions, antidepressants do not increase proliferation of neural precursor cells derived from the adult DG. Because previous studies showed that antidepressants increase the expression and secretion of glial cell line-derived neurotrophic factor (GDNF) in C6 glioma cells derived from rat astrocytes and GDNF increases neurogenesis in adult DG in vivo, we investigated the effects of GDNF on the proliferation, differentiation and apoptosis of cultured neural precursor cells derived from the adult DG. Data showed that GDNF facilitated the differentiation of neural precursor cells into astrocytes but had no effect on their proliferation or apoptosis. Moreover, GDNF increased the phosphorylation of STAT3, and both a specific inhibitor of STAT3 and lentiviral shRNA for STAT3 decreased their differentiation into astrocytes. Taken together, our findings suggest that GDNF facilitates astrogliogenesis from neural precursor cells in adult DG through activating STAT3 and that this action might indirectly affect neurogenesis.

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“…Although it remains unclear how adult neurogenesis in DG is decreased in these models, reports of some studies have suggested that glucocorticoids are involved in them (Cameron and McKay, 1999;Kim JB et al, 2004). We have already shown that Li has no effect on ADP proliferation but recovers ADP proliferation decreased by dexamethasone (DEX), a specific agonist of glucocorticoid receptor (Boku et al, 2009).…”

Section: Effects Of Mood Stabilizers On Adp Proliferationmentioning

confidence: 99%

Effects of mood stabilizers on adult dentate gyrus-derived neural precursor cells

Boku¹,

Nakagawa²,

Masuda³

et al. 2011

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Neurogenesis in the adult dentate gyrus (DG) is considered to be partly involved in the action of mood stabilizers. However, it remains unclear how mood stabilizers affect neural precursor cells in adult DG. We have established a culture system of adult rat DG-derived neural precursor cells (ADP) and have shown that lithium, a mood stabilizer, and dexamethasone, an agonist of glucocorticoid receptor, reciprocally regulate ADP proliferation. Neurogenesis constitutes not only proliferation of neural precursor cells but also apoptosis and differentiation. To develop further understanding of mood stabilizer effects on neural precursor cells in adult DG, we investigated and compared the effects of four common mood stabilizers--lithium, valproate, carbamazepine, and lamotrigine--on ADP proliferation, apoptosis, and differentiation. ADP proliferation, decreased by dexamethasone, was examined using Alamar Blue assay. Using TUNEL assay, ADP apoptosis induced by staurosporine was examined. The differentiated ADP induced by retinoic acid was characterized by immunostaining with anti-GFAP or anti-Tuj1 antibody. Lithium and valproate, but not carbamazepine and lamotrigine, recovered ADP proliferation decreased by dexamethasone. All four mood stabilizers decreased ADP apoptosis.Retinoic acid differentiated ADP into both neurons and astrocytes. Lithium and carbamazepine increased the ratio of neurons and decreased that of astrocytes. However, valproate and lamotrigine increased the ratio of astrocytes and decreased that of neurons. Therefore, these four stabilizers exhibited both common and differential effects on ADP proliferation, apoptosis, and differentiation.

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Dexamethasone inhibits proliferation of adult hippocampal neurogenesis in vivo and in vitro

Cited by 131 publications

References 29 publications

Leptin Increases Adult Hippocampal Neurogenesis in Vivo and in Vitro

Leptin Increases Adult Hippocampal Neurogenesis in Vivo and in Vitro

GDNF facilitates differentiation of the adult dentate gyrus-derived neural precursor cells into astrocytes via STAT3

Effects of mood stabilizers on adult dentate gyrus-derived neural precursor cells

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