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, Oct 08, 2015
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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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    ABSTRACT: This study evaluated the effects of Tualang honey on the medial prefrontal cortex (mPFC) morphology and the brain cholinergic system in stressed ovariectomised (OVX) rats. Sixty female Sprague-Dawley rats were divided into six groups: (i) unstressed sham-operated control rats, (ii) stressed sham-operated control rats, (iii) nonnstressed OVX rats, (iv) stressed OVX rats, (v) stressed OVX rats treated with 17 β-oestradiol (20 µg daily, sc) and (vi) stressed OVX rats treated with Tualang honey (0.2 g/kg body weight, orally). After social instability stress, the rats were sacrificed, and the right and left brain hemispheres were isolated for histological studies and estimation of acetylcoline (ACh) and acetylcholinesterase (AChE) concentrations. Stressed OVX rats showed reduced concentrations of ACh and increased AChE in the brain homogenates compared with nonstressed sham-operated controls and the effects were reversed after treatment with either 17 β-oestradiol or Tualang honey. The arrangement and number of Nissl positive cells in the mPFC neurons were significantly improved in stressed OVX rats treated with either 17 β-oestradiol or Tualang honey compared to untreated stressed OVX rats. In conclusion, treatment with either 17 β-oestradiol or Tualang honey significantly improved the morphology of mPFC, increased ACh and reduced AChE concentrations in stressed ovariectomised rats. Industrial relevance. Although the currently available hormone replacement therapy is valuable in the management of postmenopausal symptoms, it needs close monitoring of the side effects. Because of this, there is a need for a safe alternative treatment to alleviate postmenopausal symptoms. In view of the fact that most natural products have little or no known side effects, coupled with previous studies reporting neuroprotective benefits of Tualang honey, it is deemed a suitable alternative therapy to alleviate some of the neurological symptoms in postmenopausal women.
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    • "Repeated restraint led to a significant decrease in BDNF levels in the HC (Naert et al., 2011; Lakshminarasimhan and Chattarji, 2012), an effect that also occurs in females (Takuma et al., 2007) and is exacerbated by ovariectromy (Takuma et al., 2007). However, some groups have failed to find any changes in BDNF levels following repeated restraint stress (Kuroda and McEwen, 1998; Rosenbrock et al., 2005; Magarinos et al., 2011), and others have suggested that the effects on BDNF levels in the HC are present but transient (Lakshminarasimhan and Chattarji, 2012). "
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    ABSTRACT: Stress has long been associated with the development of neuropsychiatric and neurological disorders. The effects of stress vary depending upon the age during which the stress is incurred, the duration and severity of the stressor, and can further be influenced by levels of circulating gonadal hormones. To date, the majority of research investigating the link between stress and pathology development has focused on stress hormone secretion, receptor activity, and their impact on neuronal development and functioning in developing and adult male and female rodents. In recent years, work has begun to focus on additional neuromodulatory systems that may be significantly impacted by stress that may explain changes in developmental and sex-based susceptibility to stress. New research targets include molecules that play a role in neuronal development and plasticity. Specifically, stress-induced alterations in growth factors such as neurotrophins, in particular brain-derived neurotrophic factor (BDNF), have been identified as a strong candidate modulating stress-associated pathology. Furthermore, changing expression of BDNF and its receptors over development and in response to circulating gonadal hormones extend the attractiveness of this candidate signaling pathway for understanding differences in susceptibility to stress. This review focuses on what is known with regard to the effects of stress on neurotrophin expression in rodents, and the varied effects of stress on BDNF levels as a function of developmental status and sex.
    Neuroscience 02/2013; 239. DOI:10.1016/j.neuroscience.2013.01.074 · 3.36 Impact Factor
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    • "Kumar et al. (2009b) reported that Al increases p53 protein expression by activating p38 MAPK to initiate apoptosis and this is accompanied by a marked inhibition of Bcl-2 and increased Bax expression. Takuma et al. (2007) showed marked decrease in the BDNF mRNA level in the hippocampus due to ovariectomy in mice. Disruption of the proinflamatory cytokine/neurotrophin balance by Al plays an important role in the neurodegenerative disease (Nagatsu et al., 2000). "
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    ABSTRACT: The current study was undertaken to elucidate a possible neuroprotective role of dehydroepiandrosterone (DHEA) against the development of Alzheimer's disease in experimental rat model. Alzheimer's disease was produced in young female ovariectomized rats by intraperitoneal administration of AlCl(3) (4.2 mg/kg body weight) daily for 12 weeks. Half of these animals also received orally DHEA (250 mg/kg body weight, three times weekly) for 18 weeks. Control groups of animals received either DHAE alone, or no DHEA, or were not ovariectomized. After such treatment the animals were analyzed for oxidative stress biomarkers such as hydrogen peroxide, nitric oxide and malondialdehyde, total antioxidant capacity, reduced glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase activities, antiapoptotic marker Bcl-2 and brain derived neurotrophic factor. Also brain cholinergic markers (acetylcholinesterase and acetylcholine) were determined. The results revealed significant increase in oxidative stress parameters associated with significant decrease in the antioxidant enzyme activities in Al-intoxicated ovariectomized rats. Significant depletion in brain Bcl-2 and brain-derived neurotrophic factor levels were also detected. Moreover, significant elevations in brain acetylcholinesterase activity accompanied with significant reduction in acetylcholine level were recorded. Significant amelioration in all investigated parameters was detected as a result of treatment of Al-intoxicated ovariectomized rats with DHEA. These results were confirmed by histological examination of brain sections. These results clearly indicate a neuroprotective effect of DHEA against Alzheimer's disease.
    Acta biochimica Polonica 12/2011; 58(4):513-20. · 1.15 Impact Factor
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