Short report
Estradiol and soy extract increase the production of new cells in the dentate gyrus of old rats

https://doi.org/10.1016/j.exger.2005.03.003Get rights and content

Abstract

In young rodents, estradiol increases cell proliferation in the dentate gyrus of the hippocampus. However, it is unknown if the old brain retains this response to estradiol. Here we assessed the generation of new cells in the dentate gyrus of old rats after administration of estradiol or a soy extract, since soy is used as an alternative to hormonal replacement therapy in postmenopausal women. In a first experiment, 12-month-old animals were ovariectomized and studied at 14, 18 or 22 months of age. The production of new cells, assessed by the incorporation of bromodeoxyuridine (BrdU), was similar in 14- and 18-month-old rats. However, there was a significant reduction in the number of BrdU-immunoreactive cells at 22 months of age. In a second experiment, 22-month-old ovariectomized animals were treated for 10 weeks with a weekly s.c. injection of 150 μg estradiol valerianate or with 60 mg/kg per day soy extract added to the drinking water. Both treatments increased significantly the production of new cells in the dentate gyrus. These findings indicate that the brains of old rats retain the ability to increase the production of new cells in response to estradiol and soy extracts.

Introduction

In agreement with animals studies, estrogen replacement therapy (ERT) has been shown to increase memory and cognitive function in healthy postmenopausal women (Wise, 2003). However, the Women's Health Initiative (WHI) randomized trial, suggests an increased risk of dementia as a result of long-lasting hormonal treatment with conjugated equine estrogen plus medroxyprogesterone acetate (Shumaker et al., 2003, Yaffe, 2003). The results of the WHI study emphasize the need for a better understanding on the effects of sex hormones in the aged brain and after a long period of gonadal hormonal deprivation. Furthermore, dietary phytoestrogens, compounds with weak estrogenic or antiestrogenic activity such as the isoflavones contained in soy extracts (Dixon, 2004), have been proposed as alternatives of HRT (Huntley and Ernst, 2004). Neuroprotective properties of soy extracts and phytoestrogens have been documented in animal and cellular models (Wang et al., 2001, Gelinas and Martinoli, 2002, Linford and Dorsa, 2002, Zhao et al., 2002, Zeng et al., 2004). However, it is unknown whether the aged brain is still responsive to the actions of these compounds. In this study, we have assessed cell proliferation in the dentate gyrus of the hippocampus of old rats after estradiol or soy extract treatments. This parameter was selected, since estradiol regulates cell proliferation in this brain area in young female rodents (Tanapat et al., 1999, Banasr et al., 2001, Ormerod and Galea, 2001). The dentate gyrus is one of the brain areas where neurogenesis is maintained through adult life in rodents. However, cell proliferation in the dentate gyrus dramatically decreases in old age (Kuhn et al., 1996) and it is unknown whether estrogens may affect this aging-associated process.

Section snippets

Material and methods

Wistar albino female rats from our in house colony (Complutense University) were raised and maintained on 12:12 h light:dark cycle. The animals were fed a normal rat chow (A.04; Panlab, Barcelona, Spain) and had free access to tap water. All procedures used in these experiments followed the European Union normative (86/609/EEC) and were approved by the Institutional Animal Care Committee of the Complutense University.

To reduce circulating sex steroid levels, animals were bilaterally

Results

Cells incorporating BrdU were found in the dentate gyrus of all studied animals (Fig. 1). BrdU-positive nuclei were found in the hilus, in the subgranular zone (SGZ) and in the inner part of the granule cell layer (GCL). BrdU cells in the SGZ/GCL were in most cases present in clusters and were always located at the border between the GCL and the hilus. BrdU-immunoreactive nuclei in this location were of bigger size than BrdU-immunoreactive nuclei in the hilus, which probably correspond to glial

Discussion

Our findings, showing a strong decrease in the number of BrdU-labeled cells in the GCL/SGZ of the dentate gyrus of Wistar rats between 18 and 22 months of age, are in agreement with previous studies reporting a decline with advancing age in hippocampal neurogenesis in rodents (Kuhn et al., 1996). Estrogen is known to promote hippocampal neurogenesis in young female rats (Tanapat et al., 1999, Banasr et al., 2001, Ormerod and Galea, 2001). Our present findings indicate that the hormone also

Acknowledgements

This study has been carried out with financial support from Comunidad de Madrid (CAM 08.5/0062/2001; 08.5/0002.2/2003), IMSERSO, MTAS 2002, Ministerio de Ciencia y Tecnología (SAF 2002-00652) and the Commission of the European Communities, specific RTD programme ‘Quality of Life and Management of Living Resources’ (QLK6-CT-2000-00179).

References (21)

There are more references available in the full text version of this article.

Cited by (47)

  • Neurobiological mechanisms underlying sex-related differences in stress-related disorders: Effects of neuroactive steroids on the hippocampus

    2019, Frontiers in Neuroendocrinology
    Citation Excerpt :

    In contrast, rats during pro-estrus/phases of high estrogen, have been shown to have increased levels of c-Fos and zif268 activation, cell proliferation, 14d cell survival and neural excitability in the DG (McClure et al., 2013; Rummel et al., 2010; Tanapat et al., 1999; Warren et al., 1995; Yagi et al., 2017). Further corroborating the first findings about a possible involvement of estrogen in regulating hippocampal neurogenesis, lowering estrogen levels via removal of ovaries, significantly reduced cell proliferation, which could be rescued by estrogen replacement (Fowler et al., 2008; Perez-Martin et al., 2005) (see Pawluski et al., 2009; Galea, 2008 for review). However, the aforementioned effect of OVX on cell proliferation is dependent on the time elapsed since OVX.

  • Sex steroids and neurogenesis

    2017, Biochemical Pharmacology
  • Effects of genistein on cognitive dysfunction and hippocampal synaptic plasticity impairment in an ovariectomized rat kainic acid model of seizure

    2016, European Journal of Pharmacology
    Citation Excerpt :

    These studies indicate that cognitive dysfunction, LTP deficit and neuronal damage by seizure in our study are consistent with previous studies and can be explained by such mechanisms. On the other hand, genistein and other SPEs similar to 17β-estradiol have neuroprotective effects (Azcoitia et al., 2006; Qian et al., 2012) and promote neuronal viability and proliferation (Pan et al., 2012; Perez-Martin et al., 2005). Genistein enhances the expression of neurotrophins such as brain-derived neurotrophic factor (Pan et al., 2012, 1999) which is an important factor for hippocampal LTP (Ying et al., 2002) and memory formation (Alonso et al., 2002).

  • Social behavior, hormones and adult neurogenesis

    2016, Frontiers in Neuroendocrinology
View all citing articles on Scopus
View full text