Ghrelin-induced hippocampal neurogenesis and enhancement of cognitive function are mediated independently of GH/IGF-1 axis: lessons from the spontaneous dwarf rats

Li, Endan; Kim, Yumi; Kim, Sehee; Park, Seungjoon

doi:10.1507/endocrj.ej13-0045

Cited by 29 publications

(28 citation statements)

References 57 publications

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“…However, only hexarelin, which acts on the ghrelin receptor, protected these progenitors from growth deprivation-induced cell death (32). Targeted deletion of ghrelin in mice reduced the number of neural progenitors in the hippocampus whereas treatment with ghrelin rescued neurogenesis through mechanisms that involve stimulation of proliferation, migration, and differentiation of neural progenitors (33,34). In the cardiovascular system, ghrelin guides migration of adult endothelial progenitor cells through receptor-mediated activation of PI3K/AKT/NO signaling (29) and induces cardiac differentiation of embryonic stem cells by a mechanism that involves activation of the ERK pathway (30).…”

Section: Discussionmentioning

confidence: 99%

“…Clinical studies have demonstrated encouraging results and improvement of myocardial function after transplantation of different types of stem cells (2,3,58,59). Nevertheless, the advancement of regenerative medicine has faced several obstacles, most of which relate to the fact that highly potent cell sources for repair, engraftment, and survival after transplantation are not definitively identified (60)(61)(62) (16,33). Similarly, preconditioning of stem cells before transplantation, by genetic modification or by priming with cytokines, growth factors, small molecules, or other pharmacological approaches, has shown significant effects on survival and engraftment (17,18,50,63,64).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that not only GH, but GH-releasing peptides such as growth hormone-releasing hormone (GHRH) and ghrelin are expressed in myocardial tissue and protect the heart from ischemia (22)(23)(24)28). In addition to their effect on differentiated cells, these hormonal mediators have also been shown to play a role in stem cell function and fate, suggesting their possible use for stimulation of endogenous CSCs or their preconditioning before transplantation (29)(30)(31)(32)(33)(34).…”

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confidence: 99%

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Agonists of growth hormone-releasing hormone stimulate self-renewal of cardiac stem cells and promote their survival

Florea

Majid

Kanashiro‐Takeuchi

et al. 2014

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

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The beneficial effects of agonists of growth hormone-releasing hormone receptor (GHRH-R) in heart failure models are associated with an increase in the number of ckit + cardiac stem cells (CSCs). The goal of the present study was to determine the presence of GHRH-R in CSCs, the effect of GHRH-R agonists on their proliferation and survival, and the mechanisms involved. We investigated the expression of GHRH-R in CSCs of different species and the effect of GHRH-R agonists on their cell proliferation and survival. GHRH-R is expressed in ckit + CSCs isolated from mouse, rat, and pig. Treatment of porcine CSCs with the GHRH-R agonist JI-38 significantly increased the rate of cell division. Similar results were observed with other GHRH-R agonists, MR-356 and MR-409. JI-38 exerted a protective effect on survival of porcine CSCs under conditions of oxidative stress induced by exposure to hydrogen peroxide. Treatment with JI-38 before exposure to peroxide significantly reduced cell death. A similar effect was observed with MR-356. Addition of GHRH-R agonists to porcine CSCs induced activation of ERK and AKT pathways as determined by increased expression of phospho-ERK and phospho-AKT. Inhibitors of ERK and AKT pathways completely reversed the effect of GHRH-R agonists on CSC proliferation. Our findings extend the observations of the expression of GHRH-R by CSCs and demonstrate that GHRH-R agonists have a direct effect on proliferation and survival of CSCs. These results support the therapeutic use of GHRH-R agonists for stimulating endogenous mechanisms for myocardial repair or for preconditioning of stem cells before transplantation.cardiac stem cells | growth hormone-releasing hormone | agonists | cell proliferation | cell survival

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Agonists of growth hormone-releasing hormone stimulate self-renewal of cardiac stem cells and promote their survival

Florea

Majid

Kanashiro‐Takeuchi

et al. 2014

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

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“…42-44 It has also been reported that ghrelin potently stimulates hippocampal neurogenesis within the DG. 45-48 The antidepressant efficacy of compounds initially categorized as neuroprotective and/or proneurogenic, however, has not yet been described. In considering the convergence of evidence linking neurogenesis with depressive-like behavior, as well as the role of ghrelin in hippocampal neurogenesis and hippocampal distribution of Ghsr , 49 we hypothesized that the antidepressant efficacy of ghrelin might relate to its proneurogenic effect.…”

Section: Introductionmentioning

confidence: 99%

The P7C3 class of neuroprotective compounds exerts antidepressant efficacy in mice by increasing hippocampal neurogenesis

Rivera

et al. 2014

Mol Psychiatry

136

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Augmenting hippocampal neurogenesis represents a potential new strategy for treating depression. Here we test this possibility by comparing hippocampal neurogenesis in depression-prone ghrelin receptor (Ghsr)-null mice to that in wild-type littermates and by determining the antidepressant efficacy of the P7C3 class of neuroprotective compounds. Exposure of Ghsr-null mice to chronic social defeat stress (CSDS) elicits more severe depressive-like behavior than in CSDS-exposed wild-type littermates, and exposure of Ghsr-null mice to 60% caloric restriction fails to elicit antidepressant-like behavior. CSDS resulted in more severely reduced cell proliferation and survival in the ventral dentate gyrus (DG) subgranular zone of Ghsr-null mice than in that of wild-type littermates. Also, caloric restriction increased apoptosis of DG subgranular zone cells in Ghsr-null mice, although it had the opposite effect in wild-type littermates. Systemic treatment with P7C3 during CSDS increased survival of proliferating DG cells, which ultimately developed into mature (NeuN+) neurons. Notably, P7C3 exerted a potent antidepressant-like effect in Ghsr-null mice exposed to either CSDS or caloric restriction, while the more highly active analog P7C3-A20 also exerted an antidepressant-like effect in wild-type littermates. Focal ablation of hippocampal stem cells with radiation eliminated this antidepressant effect, further attributing the P7C3 class antidepressant effect to its neuroprotective properties and resultant augmentation of hippocampal neurogenesis. Finally, P7C3-A20 demonstrated greater proneurogenic efficacy than a wide spectrum of currently marketed antidepressant drugs. Taken together, our data confirm the role of aberrant hippocampal neurogenesis in the etiology of depression and suggest that the neuroprotective P7C3-compounds represent a novel strategy for treating patients with this disease.

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“…The impairment that male and female GSK3 KI mice displayed in this spatial task also was not improved by acute TDZD-8 pretreatment. Previous studies have described concurrent enhanced spatial memory and increased NPC proliferation after EE (Okun et al, 2010; Li et al, 2011; Kato et al, 2014), and concurrent impaired spatial memory and impaired NPC proliferation (Umka et al, 2010; Li et al, 2013; Nam et al, 2013; Ambrée et al, 2014; Chen et al, 2014; Greene-Schloesser et al, 2014; Valero et al, 2014). However, studies of the dependence of cognitive behaviors on NPC proliferation have often relied on correlations or have used NPC-ablating approaches, whereas in the present study EE was used to increase NPC proliferation.…”

Section: Discussionmentioning

confidence: 96%

Impairments in cognition and neural precursor cell proliferation in mice expressing constitutively active glycogen synthase kinase-3

Pardo

King

Pérez-Costas

et al. 2015

Front. Behav. Neurosci.

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Brain glycogen synthase kinase-3 (GSK3) is hyperactive in several neurological conditions that involve impairments in both cognition and neurogenesis. This raises the hypotheses that hyperactive GSK3 may directly contribute to impaired cognition, and that this may be related to deficiencies in neural precursor cells (NPC). To study the effects of hyperactive GSK3 in the absence of disease influences, we compared adult hippocampal NPC proliferation and performance in three cognitive tasks in male and female wild-type (WT) mice and GSK3 knockin mice, which express constitutively active GSK3. NPC proliferation was ~40% deficient in both male and female GSK3 knockin mice compared with WT mice. Environmental enrichment (EE) increased NPC proliferation in male, but not female, GSK3 knockin mice and WT mice. Male and female GSK3 knockin mice exhibited impairments in novel object recognition, temporal order memory, and coordinate spatial processing compared with gender-matched WT mice. EE restored impaired novel object recognition and temporal ordering in both sexes of GSK3 knockin mice, indicating that this repair was not dependent on NPC proliferation, which was not increased by EE in female GSK3 knockin mice. Acute 1 h pretreatment with the GSK3 inhibitor TDZD-8 also improved novel object recognition and temporal ordering in male and female GSK3 knockin mice. These findings demonstrate that hyperactive GSK3 is sufficient to impair adult hippocampal NPC proliferation and to impair performance in three cognitive tasks in both male and female mice, but these changes in NPC proliferation do not directly regulate novel object recognition and temporal ordering tasks.

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Ghrelin-induced hippocampal neurogenesis and enhancement of cognitive function are mediated independently of GH/IGF-1 axis: lessons from the spontaneous dwarf rats

Cited by 29 publications

References 57 publications

Agonists of growth hormone-releasing hormone stimulate self-renewal of cardiac stem cells and promote their survival

Agonists of growth hormone-releasing hormone stimulate self-renewal of cardiac stem cells and promote their survival

The P7C3 class of neuroprotective compounds exerts antidepressant efficacy in mice by increasing hippocampal neurogenesis

Impairments in cognition and neural precursor cell proliferation in mice expressing constitutively active glycogen synthase kinase-3

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