17β-Estradiol attenuates hippocampal neuronal loss and cognitive dysfunction induced by chronic restraint stress in ovariectomized rats

Laboratory of Neuropsychopharmacology, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Neuroscience (Impact Factor: 3.36). 05/2007; 146(1):60-8. DOI: 10.1016/j.neuroscience.2007.01.017
Source: PubMed


Several lines of evidence suggest that hormonal changes after menopause may play an important role in the incidence of cognitive dysfunction, and also in the development of Alzheimer's disease. In this study, we investigated the effect of estrogen on cognitive function in rats under different stress environment. Female rats were divided into four groups: two groups were ovariectomized (OVX) and two were sham-operated. One group each of OVX and sham rats was kept in a normal environment, and the other groups were assigned to a daily restraint stress (6 h/day) for 21 days from 2 months after the operation. Following the stress period, subjects were tested for performance in novel object recognition test and then used for morphological and neurochemical analyses. The OVX plus stress (OVX/stress) group showed a significant impairment of recognition of novel objects, compared with the other groups. The OVX/stress group also showed a marked decrease in the number of pyramidal cells of the CA3 region and levels of brain-derived neurotrophic factor mRNA in the hippocampus. We further examined the effect of estrogen against cognitive dysfunction and hippocampal changes of OVX/stress rats. Vehicle or 17beta-estradiol (E2) at 20 microg/day was s.c. administered to OVX/stress rats from 2 days before the stress period to the end of behavioral analysis through an implantable osmotic pump. Chronic E2 treatment decreased stress response and improved the cognitive and morphological impairments relative to vehicle group. These data have important implications for cognition enhancing effect of estrogen treatment in postmenopausal women.

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Available from: Kazuhiro Takuma
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    • "In addition, there are reports demonstrating that (in females) estrogen may have a role in tactile learning. Takuma et al. reported the impairment of recognition memory (assessed by NORT) in ovariectomized rats (Takuma et al. , 2007b). A decline in the production of ovarian hormones such as estrogen during menopause, is associated with a greater risk of memory decline, including mild cognitive impairment and Alzheimer's disease (Lebrun et al. , 2005, Pinkerton andHenderson, 2005), and estrogen replacement therapy has been shown to play an important role in the improvement of cognitive function in postmenopausal women (Genazzani et al. , 2007, Hogervorst et al. , 2000). "
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    • "Repeated or chronic exposure to stressful stimuli causes a sustained increase in levels of glucocorticoid by impaired negative-feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in an insult to susceptible neural tissues. Among limbic structures, the hippocampus is vulnerable to stress (Watanabe et al., 1992; Takuma et al., 2007; Kim et al., 2011). Evidence has indicated morphological and biological changes to the hippocampus, including stress-induced atrophy of dendritic processes, reduced expression of brain-derived Tae-Kyung Han and Jang-Kyu Lee contributed equally to this work. "
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    ABSTRACT: We assessed whether chronic treadmill exercise attenuated the depressive phenotype induced by restraint stress in ovariectomized mice (OVX). Immobility of OVX in the forced swimming test was comparable to that of sham mice (CON) regardless of the postoperative time. Immobility was also no difference between restrained mice (exposure to periodic restraint for 21 days; RST) and control mice (CON) on post-exposure 2nd and 9th day, but not 15th day. In contrast, the immobility of ovariectomized mice with repeated stress (OVX + RST) was profoundly enhanced compared to ovariectomized mice-alone (OVX), and this effect was reversed by chronic exercise (19 m/min, 60 min/day, 5 days/week for 8 weeks; OVX + RST + Ex) or fluoxetine administration (20 mg/kg, OVX + RST + Flu). In parallel with behavioral data, the immunoreactivity of Ki-67 and doublecortin (DCX) in OVX was significantly decreased by repeated stress. However, the reduced numbers of Ki-67- and DCX-positive cells in OVX + RST were restored in response to chronic exercise (OVX + RST + Ex) and fluoxetine (OVX + RST + Flu). In addition, the expression pattern of cAMP response element-binding protein (CREB) and calcium-calmodulin-dependent kinase IV (CaMKIV) was similar to that of the hippocampal proliferation and neurogenesis markers (Ki-67 and DCX, respectively). These results suggest that menopausal depression may be induced by an interaction between repeated stress and low hormone levels, rather than a deficit in ovarian secretion alone, which can be improved by chronic exercise.
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    • "The rats were treated with either subcutaneous injection of 17 β-oestradiol 20 µg/day (Cayman Chemical, Ann Arbor, MI, USA) in 2.5 µl of corn oil (Takuma et al. 2007) or oral gavage of 0.2 g/kg body weight/day (Zaid et al. 2010) Tualang honey (Agro Mas, Mergong, Kedah, Malaysia) 3 days prior to the procedure and continued throughout the 15 days of treatment. "
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