Article

Progesterone inhibits estrogen-mediated neuroprotection against excitotoxicity by down-regulating estrogen receptor-β

Wiley
Journal of Neurochemistry
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Abstract

J. Neurochem. (2010) 115, 1277–1287. While both 17β-estradiol (E2) and progesterone (P4) are neuroprotective in several experimental paradigms, P4 also counteracts E2 neuroprotective effects. We recently reported that a 4-h treatment of cultured hippocampal slices with P4 following a prolonged (20 h) treatment with E2 eliminated estrogenic neuroprotection against NMDA toxicity and induction of brain-derived neurotrophic factor (BDNF) expression. In the present study, we evaluated the effects of the same treatment on levels of estrogen receptors, ERα and ERβ, and BDNF using a similar paradigm. E2 treatment resulted in elevated ERβ mRNA and protein levels, did not modify ERα mRNA, but increased ERα protein levels, and increased BDNF mRNA levels. P4 reversed E2-elicited increases in ERβ mRNA and protein levels, in ERα protein levels, and in BDNF mRNA levels. Experiments with an ERβ-specific antagonist, PHTPP, and specific agonists of ERα and ERβ, propylpyrazoletriol and diarylpropionitrile, respectively, indicated that E2-mediated neuroprotection against NMDA toxicity was, at least in part, mediated via ERβ receptor. In support of this conclusion, E2 did not protect against NMDA toxicity in cultured hippocampal slices from ERβ−/− mice. Thus, E2-mediated neuroprotection against NMDA toxicity may be because of estrogenic induction of BDNF via its ERβ receptor, and P4-mediated inhibition of E2 neuroprotective effects treatment to P4-induced down-regulation of ERβ and BDNF.

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... An accumulating body of research demonstrates that, as in the endometrium, P4 can block some E2 actions in brain. For example, P4 treatment can largely prevent E2-induced increases of anti-apoptotic factors and neurotrophins (Aguirre et al., 2010, Bimonte-Nelson, 2004, Garcia-Segura, 1998) as well as E2-mediated neuroprotection against excitotoxicity (Rosario, 2006) and Aβ accumulation (Carroll et al., 2007). P4 can also block E2-mediated increases in CREB phosphorylation and spine density when co-administered with E2 Segal, 1996, 2000). ...
... Several studies have established the role of BDNF in E2-mediated neuroprotection (Baudry et al., 2013). Prior work has demonstrated that P4 attenuates E2 neuroprotection by decreasing ER expression and ER-mediated increase in BDNF expression (Aguirre et al., 2010, Aguirre andBaudry, 2009). To evaluate the contribution of this pathway to the observed effects of the progestagens on apoptosis and on E2 neuroprotection, we examined their effects on BDNF mRNA levels. ...
... In previous studies, we demonstrated inhibitory effects of P4 on ER expression and function as well as attenuation of E2-induced neuroprotection and BDNF expression (Aguirre et al., 2010, Aguirre and Baudry, 2009, Jayaraman and Pike, 2009). In the current study, we investigated the effect of seven clinically relevant, synthetic progestagens on the expression levels of ERα, ERβ, and BDNF, E2-mediated neuroprotection against apoptosis and E2induced BDNF expression. ...
Article
Progesterone and other progestagens are used in combination with estrogens for clinical purposes, including contraception and postmenopausal hormone therapy. Progesterone and estrogens have interactive effects in brain, however interactions between synthetic progestagens and 17β-estradiol (E2) in neurons are not well understood. In this study, we investigated the effects of seven clinically relevant progestagens on estrogen receptor (ER) mRNA expression, E2-induced neuroprotection, and E2-induced BDNF mRNA expression. We found that medroxyprogesterone acetate decreased both ERα and ERβ expression and blocked E2-mediated neuroprotection and BDNF expression. Conversely, levonorgestrel and nesterone increased ERα and or ERβ expression, were neuroprotective, and failed to attenuate E2-mediated increases in neuron survival and BDNF expression. Other progestagens tested, including norethindrone, norethindrone acetate, norethynodrel, and norgestimate, had variable effects on the measured endpoints. Our results demonstrate a range of qualitatively different actions of progestagens in cultured neurons, suggesting significant variability in the neural effects of clinically utilized progestagens.
... ASD patients have elevated steroidogenic activity (9), and cholesterol metabolism, various steroid abnormalities, and vitamin D metabolism are involved in ASD development (10,11). In addition, oral contraceptives have been reported to be associated with ASD prevalence (12,13), as progesterone suppresses ERβ expression (14,15). Progestin can also regulate neurogenic responses (16) and impair cognitive response during development (17) by down-regulating ERβ expression (18,19). ...
... It has been reported that ERβ dysregulation in the brain has been found in ASD subjects (20), and, very interestingly, we have recently reported that prenatal exposure of either levonorgestrel (LNG) (19) or any of the other 8 kinds of synthetic progestins (21) induces autism-like behavior in offspring through ERβ suppression in rats (19,21). This indicates that prenatal progestin exposure, together with subsequent maternal hormone dysfunction, may result in ERβ downregulation and contribute to ASD development (14,15). We hypothesize that prenatal progestin exposure is a risk factor for ASD development through ERβ downregulation in the brain. ...
Article
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We have previously reported that prenatal progestin exposure induces autism-like behavior in offspring through ERβ (estrogen receptor β) suppression in the brain, indicating that progestin may induce autism spectrum disorders (ASD). In this study, we aim to investigate whether prenatal progestin exposure is associated with ASD. A population-based case-control epidemiology study was conducted in Hainan province of China. The ASD children were first screened with the Autism Behavior Checklist (ABC) questionnaire, and then diagnosed by clinical professionals using the ASD diagnosis criteria found in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). Eventually, 235 cases were identified as ASD from 37863 children aged 0–6 years old, and 682 matched control subjects with typically developing children were selected for the analysis of potential impact factors on ASD prevalence using multivariate logistic regression. Our data show that the ASD prevalence rate in Hainan was 0.62% with a boy:girl ratio of 5.4:1. Interestingly, we found that the following factors were strongly associated with ASD prevalence: use of progestin to prevent threatened abortion, use of progestin contraceptives at the time of conception, and prenatal consumption of progestin-contaminated seafood during the first trimester of pregnancy. All the above factors were directly or indirectly involved with prenatal progestin exposure. Additionally, we conducted in vivo experiments in rats to further confirm our findings. Either endogenous (progesterone) or synthetic progestin (norethindrone)-treated seafood zebrafish were used to feed pregnant dams, and the subsequent offspring showed autism-like behavior, which further demonstrated that prenatal progestin exposure may induce ASD. We conclude that prenatal progestin exposure may be associated with ASD development.
... Our recent analyses found that both BDNF and TrkB protein levels were significantly reduced in the hippocampus of ERβ but not ERα knockout adult mice. Additional studies demonstrated that ERβ was necessary for estrogen-mediated upregulation of BDNF in both neuronal cells and brain tissues, and activation of ERβ induced a robust increase in BDNF protein level in experimentally-induced menopausal mouse brains (Aguirre et al., 2010;Aguirre and Baudry, 2009;Zhao et al., 2011a). ...
... These differential regulatory patterns present an optimal opportunity for an ERβ-selective agonist to reap the health benefits associated with ERβ without activating untoward effects mediated by ERα (Zhao and Brinton, 2006a). Moreover, the lack of uterotrophic activity associated with an ERβ agonist eliminates the need to combine with a progestogen in the treatment, which has been proven as a compounding factor for the effectiveness of ET, for example, the presence of a progestogen and a different treatment schedule could exert an inhibitory effect against estrogen-mediated neural responses (Aguirre et al., 2010;Nilsen et al., 2005;Zhao et al., 2012). Together, these therapeutic advantages make ERβ a promising and safe target for the development of therapeutic agents that could benefit various indications in which ERβ plays a role. ...
... They detected that progesterone was able to blocks the increase in CREB phosphorylation and prevent estradiol-induced increase in cell activity and spine density. In line, Aguirre et al., [82] showed that progesterone reverses estradiol-induced increase in ER and BDNF levels, and eliminates estradiol effect against glutamatergic excitotoxicity in hippocampal cultures. It seems that progesterone inhibition on CREB activity has a negative influence on estradiol effects on BDNF in GABAergic neurons. ...
Preprint
Sex steroids and brain-derived neurotrophic factor (BDNF) participate in neural tissue formation, phenotypic differentiation, and neuroplasticity. All these processes are essential for the health and maintenance of the central nervous system. Aim: To elucidate the interaction mechanisms between BDNF and sex steroids in neuronal function. Method: A series of searches were performed using the Mesh terms for androgen/receptor, estrogens/receptors, and BDNF/receptor, and a collection of the scientific data available on PubMed up to February 2022, on the mechanical interactions between BDNF and sex steroids was included in this literature review. Discussion: Sex steroids influence the formation and/or maintenance of neural circuits via different mechanisms, including the regulation of BDNF expression and signaling. Estrogens exert a time- and region-specific effect on BDNF synthesis. The nuclear estrogen receptor can directly regulate BDNF expression, independently of estrogen presence, in neuronal cells; whereas, progesterone and testosterone upregulate BDNF expression via their specific nuclear receptors. In addition, testosterone has a positive effect on BDNF release by glial cells, which lack androgen receptors.
... Previous studies provided possible explanations for these findings. Several preclinical studies have shown that progesterone counteracts estrogen-mediated neuroprotection [30][31][32], which suggests that it may accelerate neurodegeneration. In addition, Strijks et al. showed that progesterone had possible antidopaminergic effects in postmenopausal women with PD [33]. ...
Article
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Background The relationship between menopausal hormone therapy (MHT) and risk of Parkinson’s disease (PD) remains controversial. Objective This nationwide population-based cohort study investigated the association between MHT and PD development. Methods Data from the National Health Insurance System of South Korea from 2007 to 2020 were used. The MHT group included women who underwent MHT for the first time between 2011–2014, while the non-MHT group included women who visited a healthcare provider for menopause during the same period but never received hormonal therapy. We used propensity score matching (1 : 1) to adjust for potential confounders, and Cox regression models to assess the association between MHT and PD. Results We selected 303,260 female participants (n = 151,630 per MHT and non-MHT groups). The median age of the participants was 50 (48–54) years, and the follow-up period lasted 7.9 (6.9–8.9) years. Cox regression analysis revealed an increased risk of PD with MHT (hazard ratio [HR] 1.377, 95% confidence interval [CI] 1.184–1.602), particularly with tibolone (HR 1.554, 95% CI 1.297–1.861) and estrogen alone (HR 1.465, 95% CI 1.054–2.036). Tibolone and estrogen alone were linked to PD within three years; however, no association was observed after three years. In contrast, the use of combined estrogen-progesterone was linked to a higher risk of PD, which increased with the duration of MHT (HR 1.885, 95% CI 1.218–2.918 for over five years). Conclusions This study demonstrated that the MHT is closely associated with the risk of PD in a regimen- and duration-specific manner.
... While little is known about ASD causes, recent evidence supported its association with estrogen receptor β (ERβ) dysregulation [162,163]. In fact, maternal hormonal exposure to ERβ inhibitors such as natural progesterone and synthetic progestin impairs cognitive flexibility and contributes to ASD development [164,165]. A study showed that prenatal exposure of rat offspring to progestins leads to decreased ERβ expression in the amygdala [166]. ...
Article
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Adverse pregnancy outcomes are considered significant health risks for pregnant women and their offspring during pregnancy and throughout their lifespan. These outcomes lead to a per-turbated in-utero environment that impacts critical phases of the fetus's life and correlates to an increased risk of chronic pathological conditions, such as diabetes, obesity, and cardiovascular diseases , in both the mother's and adult offspring's life. The dietary intake of naturally occurring anti-oxidants promotes health benefits and disease prevention. In this regard, maternal dietary intake of polyphenolic antioxidants is linked to a reduced risk of maternal obesity and cardio-metabolic disorders , positively affecting both the fetus and offspring. In this work, we will gather and critically appraise the current literature highlighting the effect/s of the naturally occurring polyphenol anti-oxidant resveratrol on oxidative stress, inflammation, and other molecular and physiological phenomena associated with pregnancy and pregnancy conditions, such as gestational diabetes, preeclampsia, and preterm labor. The resveratrol impact on prenatal complications and pregnancy-associated structures, such as the fetus and placenta, will also be discussed. Finally, we will draw conclusions from the current knowledge and provide future perspectives on potentially exploiting resveratrol as a therapeutic tool in pregnancy-associated conditions.
... In the reported animal studies, 17βestradiol and progesterone [64] or progesterone alone [63] did not influence mAChRs expression levels. On the contrary, some studies suggest that progesterone may counteract the effects of estrogens [73]. (SPET) ↑ [74] The effect of 17β-estradiol and progesterone on the expression of mAChRs in the brain. ...
Article
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Muscarinic acetylcholine receptors expressed in the central nervous system mediate various functions, including cognition, memory, or reward. Therefore, muscarinic receptors represent potential pharmacological targets for various diseases and conditions, such as Alzheimer’s disease, schizophrenia, addiction, epilepsy, or depression. Muscarinic receptors are allosterically modulated by neurosteroids and steroid hormones at physiologically relevant concentrations. In this review, we focus on the modulation of muscarinic receptors by neurosteroids and steroid hormones in the context of diseases and disorders of the central nervous system. Further, we propose the potential use of neuroactive steroids in the development of pharmacotherapeutics for these diseases and conditions.
... 50 The underlying molecular mechanism for this phenomenon was examined in a follow-up investigation: the estradiol-dependent increases in protein levels of estrogen receptors and brain-derived neurotrophic factor (BDNF), a neurotrophin with potent neuroprotective effects, were reversed by co-administration with progesterone. 51 Estradiol and progesterone have also been shown to have, at times, opposing effects on astrogliosis, depending on the region and injury model. 52 In the present study, we observed a diverging association between progesterone and levels of NfL and GFAP and the absence of an association between estradiol and blood biomarker levels, which could potentially be attributed to the complexity of the interaction between estradiol and progesterone. ...
Article
Recent investigations have identified water polo athletes as at risk for concussions and repetitive subconcussive head impacts. However, head impact exposure in collegiate varsity women's water polo has not yet been longitudinally quantified. We aimed to determine the relationship between cumulative and acute head impact exposure across preseason training and changes in serum biomarkers of brain injury. Twenty-two Division I collegiate women's water polo players were included in this prospective observational study. They wore sensor-installed mouthguards during all practices and scrimmages during eight weeks of preseason training. Serum samples were collected at six time points (at baseline, before and after scrimmages during week 4 and 7, and after the eight-week preseason training period) and assayed for neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) using Simoa® Human Neurology 2-Plex B assay kits. Serum GFAP increased over time (e.g., an increase of 0.6559 pg/mL per week; p = 0.0087). However, neither longitudinal nor acute pre-post scrimmage changes in GFAP were associated with head impact exposure. Contrarily, an increase in serum NfL across the study period was associated with cumulative head impact magnitude (sum of peak linear acceleration: B = 0.015, SE = 0.006, p = 0.016; sum of peak rotational acceleration: B = 0.148, SE = 0.048, p = 0.006). Acute changes in serum NfL were not associated with head impacts recorded during the two selected scrimmages. Hormonal contraceptive use was associated with lower serum NfL and GFAP levels over time, and elevated salivary levels of progesterone were also associated with lower serum NfL levels. These results suggest that detecting increases in serum NfL may be a useful way to monitor cumulative head impact burden in women's contact sports and that female-specific factors, such as hormonal contraceptive use and circulating progesterone levels, may be neuroprotective, warranting further investigations.
... It was found that E2 enhances NR2B expression, a subunit of NMDAR, and accordingly enhances long-term potentiation (LTP) in the learning and memory process [135,136]. Liu et al., 2008 found that LTP enhancement was directly mediated through ERβ activation [137], and ERβ lacking mice (ERβ-/-) failed to show E2 mediated neuroprotection against NMDA-induced excitotoxicity [138]. The evidence further suggests that E2-mediated neuroprotection reduces ischemia-induced excitotoxicity through interaction with the NMDA receptor [139,140]. ...
Article
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Radiation for medical use is a well-established therapeutic method with an excellent prognosis rate for various cancer treatments. Unfortunately, a high dose of radiation therapy comes with its own share of side effects, causing radiation-induced non-specific cellular toxicity; consequently, a large percentage of treated patients suffer from chronic effects during the treatment and even after the post-treatment. Accumulating data evidenced that radiation exposure to the brain can alter the diverse cognitive-related signalings and cause progressive neurodegeneration in patients because of elevated oxidative stress, neuroinflammation, and loss of neurogenesis. Epidemiological studies suggested the beneficial effect of hormonal therapy using estrogen in slowing down the progression of various neuropathologies. Despite its primary function as a sex hormone, estrogen is also renowned for its neuroprotective activity and could manage radiation-induced side-effects as it regulates many hallmarks of neurodegenerations. Thus, treatment with estrogen and estrogen-like molecules or modulators, including phytoestrogens, might be a potential approach capable of neuroprotection in radiation-induced brain degeneration. This review summarized the molecular mechanisms of radiation effects and estrogen signaling in the manifestation of neurodegeneration and highlighted the current evidence on the phytoestrogen mediated protective effect against radiation-induced brain injury. This existing knowledge points towards a new area to expand to identify the possible alternative therapy that can be taken with radiation therapy as adjuvants to improve patients' quality of life with compromised cognitive function.
... Experiments with PHTPP, indicated that E2mediated neuroprotection against NMDA toxicity was mediated via ERβ receptor (37). Many studies have reported a primary role for ERα as a regulator of the anti-inflammatory properties of estradiol, including the anti-inflammatory and neuroprotective activity of estradiol (38), neuroprotection after ischemia and inhibition of microglial activation (39). Studies involving transgenic mice with targeted deletion of either ERα or Erβ indicate that ERα, but not ERβ, is required for the E2-mediated suppression of BBB permeability (8). ...
Article
Objective(s): Estrogen (E2) has neuroprotective effects on blood-brain-barrier (BBB) after traumatic brain injury (TBI). In order to investigate the roles of estrogen receptors (ERs) in these effects, ER-α antagonist (MPP) and, ER-β antagonist (PHTPP), or non-selective estrogen receptors antagonist (ICI 182780) were administered. Materials and Methods: Ovariectomized rats were divided into 10 groups, as follows: Sham, TBI, E2, oil, MPP+E2, PHTPP+E2, MPP+PHTPP+E2, ICI+E2, MPP, and DMSO. E2 (33.3 µg/Kg) or oil were administered 30 min after TBI. 1 dose (150 µg/Kg) of each of MPP, PHTPP, and (4 mg/kg) ICI182780 was injected two times, 24 hr apart, before TBI and estrogen treatment. BBB disruption (Evans blue content) and brain edema (brain water content) evaluated 5 hr and 24 hr after the TBI were evaluated, respectively. Results: The results showed that E2 reduced brain edema after TBI compared to vehicle (P<0.01). The brain edema in the MPP+E2 and PHTPP+E2 groups decreased compared to the vehicle (P<0.001). There was no significant difference in MPP+PHTPP+E2 and ICI+E2 compared to TBI. This parameter in MPP was similar to vehicle. Evans blue content in E2 group was lower than vehicle (P<0.05).The inhibitory effect of E2 on Evans blue was not reduced by MPP+E2 and PHTPP+E2 groups, but decreased by treatment with MPP+PHTPP or ICI. MPP had no effect on Evans blue content. Conclusion: A combined administration of MPP and PHTPP or ICI inhibited the E2-induced decrease in brain edema and BBB disruption; this may suggest that these effects were mediated via both receptors.
... Besides, a number of studies demonstrated that ERs and PRs interacted with neuro-nutrients, such as BDNF, stimulated the synthesis of proteins that required for neuronal differentiation and maintenance [54]. It had been found that at least a proportion of ERs played a key role in neuroprotection and inhibition of NMDA neurotoxicity and the induction of BDNF receptors [55]. The ERα and ERβ receptors agonist could prevent oxidative brain damage and cognitive impairment by up-regulating levels of cAMP response element-binding protein (CREB) and BDNF in the hippocampus [56]. ...
Article
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Background Progestational stress has been proven to be a risk for the neural development of offspring, especially in the hippocampus. However, whether Chaihu Shugan San (CSS) can ameliorate hippocampal neural development via the regulation of brain-derived neurotrophic factor (BDNF), and N-methyl-D-aspartate receptors (NMDAR) 2A (NR2A) and 2B (NR2B), and the mechanism of such action remains unclear. Methods Thirty-six female rats were randomly allocated into control, chronic immobilization stress (CIS) and CSS groups according to the random number table, respectively. The male offspring were fed for 21 days after birth then randomly divided into the same three groups (6 rats/group) as the female rats. Female rats, except for the control group, underwent 21-day CIS to established a progestational stress anxiety-like model which was evaluated by body weight, the elevated plus-maze (EPM) test and serum dopamine (DA) measured using an enzyme-linked immunosorbent assay (ELISA). The expression levels of estrogen receptors (ERα/ERβ) and progesterone receptor (PR) in female rat ovaries were quantified by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. The hippocampal tissue in the 21-day offspring was observed by hematoxylin-eosin (HE) staining. The concentration of BDNF, NR2A, and NR2B were measured by RT-qPCR and immunohistochemistry in the CA3 and dentate gyrus (DG) regions of offsprings’ hippocampus. Results Compared with the female control group, significant differences in body weight, EPM test and DA concentration were observed in the CIS group, meanwhile, the concentration of ERα (P < 0.05), PR (P < 0.05) and ERβ in the ovaries were decreased. In the offsprings’ hippocampus of the CIS group, the chromatin of the nucleus was edge set and with condensed and irregular morphology nucleus, and the cytoplasm was unevenly stained with spaces around the cells, moreover, the expression levels of BDNF, NR2A, and NR2B were also declined (P < 0.05). However, Chaihu Shugan San reversed these changes, especially the BDNF in the DG region (P < 0.05), and NR2A and NR2B in the CA3 and DG region (P < 0.05). Conclusions CSS could ameliorate the neural development of the hippocampus in offspring damaged by anxiety-like progestational stress in female rats via regulating the expression levels of ERα, ERβ, and PR in female rat ovaries and BDNF, NR2A, and NR2B in the hippocampus of their offspring.
... The role of ESR2 in the development and progression of Alzheimer 's disease (AD) has been well accepted [99,100]. ESR2 is important for synaptic plasticity and LTP via its regulation of brain-derived neurotrophic factor (BDNF) [101,102]. Overexpression of ESR2 in a rat model of AD reduced amyloid-β deposition in the hippocampus and improved the learning and memory of AD rats [99]. ...
Article
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The HECT (Homologous to the E6-AP Carboxyl Terminus)-family protein E6AP (E6-associated protein), encoded by the UBE3A gene, is a multifaceted ubiquitin ligase that controls diverse signaling pathways involved in cancer and neurological disorders. The oncogenic role of E6AP in papillomavirus-induced cancers is well known, with its action to trigger p53 degradation in complex with the E6 viral oncoprotein. However, the roles of E6AP in non-viral cancers remain poorly defined. It is well established that loss-of-function alterations of the UBE3A gene cause Angelman syndrome, a severe neurodevelopmental disorder with autosomal dominant inheritance modified by genomic imprinting on chromosome 15q. Moreover, excess dosage of the UBE3A gene markedly increases the penetrance of autism spectrum disorders, suggesting that the expression level of UBE3A must be regulated tightly within a physiologically tolerated range during brain development. In this review, current the knowledge about the substrates of E6AP-mediated ubiquitination and their functions in cancer and neurological disorders is discussed, alongside with the ongoing efforts to pharmacologically modulate this ubiquitin ligase as a promising therapeutic target.
... It should be noted that competing hormonal factors may also affect BDNF function. For example, progesterone [44] can act as a glucocorticoid agonist [45], can regulate BDNF [46], can block estradiol's neuroprotective effects by downregulating estrogen receptor β [47], and can prevent BDNF induction by estradiol [48]. Thus, understanding the effects of such additional hormonal factors on BDNF function is a particular priority. ...
Article
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Brain-derived neurotrophic factor (BDNF) is widely accepted for its involvement in resilience and antidepressant drug action, is a common genetic locus of risk for mental illnesses, and remains one of the most prominently studied molecules within psychiatry. Stress, which arguably remains the "lowest common denominator" risk factor for several mental illnesses, targets BDNF in disease-implicated brain regions and circuits. Altered stress-related responses have also been observed in animal models of BDNF deficiency in vivo, and BDNF is a common downstream intermediary for environmental factors that potentiate anxiety-and depressive-like behavior. However, BDNF's broad functionality has manifested a heterogeneous literature; likely reflecting that BDNF plays a hitherto under-recognized multifactorial role as both a regulator and target of stress hormone signaling within the brain. The role of BDNF in vulnerability to stress and stress-related disorders, such as posttraumatic stress disorder (PTSD), is a prominent example where inconsistent effects have emerged across numerous models, labs, and disciplines. In the current review we provide a contemporary update on the neurobiology of BDNF including new data from the behavioral neuroscience and neuropsychiatry literature on fear memory consolidation and extinction, stress, and PTSD. First we present an overview of recent advances in knowledge on the role of BDNF within the fear circuitry, as well as address mounting evidence whereby stress hormones interact with endogenous BDNF-TrkB signaling to alter brain homeostasis. Glucocorticoid signaling also acutely recruits BDNF to enhance the expression of fear memory. We then include observations that the functional common BDNF Val66Met polymorphism modulates stress susceptibility as well as stress-related and stress-inducible neuropsychiatric endophenotypes in both man and mouse. We conclude by proposing a BDNF stress-sensitivity hypothesis, which posits that disruption of endogenous BDNF activity by common factors (such as the BDNF Val66Met variant) potentiates sensitivity to stress and, by extension, vulnerability to stress-inducible illnesses. Thus, BDNF may induce plasticity to deleteriously promote the encoding of fear and trauma but, conversely, also enable adaptive plasticity during extinction learning to suppress PTSD-like fear responses. Ergo regulators of BDNF availability, such as the Val66Met polymorphism, may orchestrate sensitivity to stress, trauma, and risk of stress-induced disorders such as PTSD. Given an increasing interest in personalized psychiatry and clinically complex cases, this model provides a framework from which to experimentally disentangle the causal actions of BDNF in stress responses, which likely interact to potentiate, produce, and impair treatment of, stress-related psychiatric disorders.
... Both receptors have been reported to decrease with age in the brain of rats and mice 9,10 . Unlike ERα, which has high distribution mainly in reproductive organs, ERβ has a prominent role in the nervous system 11,12 . Considering the side effect of ERα activation on reproductive organs under estrogen therapy 13 , selective activation of ERβ has been regarded as a potential valid target for AD therapy. ...
Article
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Alzheimer’s Disease (AD) is the most common neurodegenerative disorder in the elderly. Beta-amyloid (Aβ) peptide accumulation is considered as a primary cause of AD pathogenesis, with defective autophagy in patients’ brains. Enhanced autophagic activity has been reported to promote Aβ clearance in vitro and in vivo models. Meanwhile, there is growing evidence that estrogen receptor β (ERβ) is a viable therapeutic target that can ameliorate the pathological features associated with AD. Very little is known about the detailed molecular mechanisms underlying the relationship between ERβ, autophagy, and Aβ degradation in AD. This study aims to uncover whether ERβ participates in autophagy and promotes extracellular Aβ1–42 degradation through the autophagy–lysosome system. Here we find that overexpression of ERβ caused autophagic activation as seen by increased microtubule-associated protein 1 light chain 3-II (LC3-II), SQSTM1 (sequestosome 1) degradation, LC3 punctate distribution, autophagosome, and autolysosome accumulation. In addition, we show that ERβ could induce autophagy through direct protein–protein interaction with ATG7 (E1-like enzyme). Furthermore, ERβ-mediated decrease in Aβ1–42 was blocked by the autophagy inhibitor chloroquine (CQ) in SH-SY5Y cells and the HEK293T (AβPPsw) model. Aβ1–42 or CQ induced cytotoxicity was restored by a selective ERβ activator diarylpropionitrile (DPN). Collectively, these data indicate that overexpression of ERβ exerts a neuroprotective effect through interacting with ATG7 protein and further enhances autophagy–lysosomal activity for Aβ1–42 clearance at the cellular level.
... In addition, natural progesterone and synthetic progestin regulate neurogenic responses [19] and impair cognitive flexibility during development [20] as well as downregulate ERβ expression [9,21]. We hypothesize that clinically relevant progestin may counteract estrogen-mediated neuroprotective effects via downregulation of ERβ, and contribute to ASD development [22,23]. ...
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Background Recent literatures indicate that maternal hormone exposure is a risk factor for autism spectrum disorder (ASD). We hypothesize that prenatal progestin exposure may counteract the neuroprotective effect of estrogen and contribute to ASD development, and we aim to develop a method to ameliorate prenatal progestin exposure-induced autism-like behavior. Methods Experiment 1: Prenatal progestin exposure-induced offspring are treated with resveratrol (RSV) through either prenatal or postnatal exposure and then used for autism-like behavior testing and other biomedical analyses. Experiment 2: Prenatal norethindrone (NET) exposure-induced offspring are treated with ERβ knockdown lentivirus together with RSV for further testing. Experiment 3: Pregnant dams are treated with prenatal NET exposure together with RSV, and the offspring are used for further testing. Results Eight kinds of clinically relevant progestins were used for prenatal exposure in pregnant dams, and the offspring showed decreased ERβ expression in the amygdala with autism-like behavior. Oral administration of either postnatal or prenatal RSV treatment significantly reversed this effect with ERβ activation and ameliorated autism-like behavior. Further investigation showed that RSV activates ERβ and its target genes by demethylation of DNA and histone on the ERβ promoter, and then minimizes progestin-induced oxidative stress as well as the dysfunction of mitochondria and lipid metabolism in the brain, subsequently ameliorating autism-like behavior. Conclusions We conclude that resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERβ activation. Our data suggest that prenatal progestin exposure is a strong risk factor for autism-like behavior. Many potential clinical progestin applications, including oral contraceptive pills, preterm birth drugs, and progestin-contaminated drinking water or seafood, may be risk factors for ASD. In addition, RSV may be a good candidate for clinically rescuing or preventing ASD symptoms in humans, while high doses of resveratrol used in the animals may be a potential limitation for human application. Electronic supplementary material The online version of this article (10.1186/s13229-018-0225-5) contains supplementary material, which is available to authorized users.
... Alternatively, it may be that overexpression of GluN2A and GluN2B subunits in BDNF het mice, particularly within the estradiol treatment group, is causing excitotoxicity, leading to impaired Y-maze performance [9]. Indeed, neuroprotective effects of estradiol against NMDA toxicity are thought to be mediated by BDNF [38]; therefore, in the absence of BDNF (BDNF heterozygous), perhaps this protection is lost. Further studies to identify whether the changes we see in GluN expression are synaptic or extrasynaptic may help to clarify this effect as previous studies suggest that the activation of synaptic GluN leads to synaptic plasticity and cell survival, while extrasynaptic activation can lead to excitotoxic cell death [39]. ...
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Sex steroid hormones have neuroprotective properties which may be mediated by brain-derived neurotrophic factor (BDNF). This study sought to determine the interactive effects of preadolescent hormone manipulation and BDNF heterozygosity ( +/− ) on hippocampal NMDA-R expression. Wild-type and BDNF +/− mice were gonadectomised, and females received either 17 β -estradiol or progesterone treatment, while males received either testosterone or dihydrotestosterone (DHT) treatment. Dorsal (DHP) and ventral hippocampus (VHP) were dissected, and protein expression of GluN1, GluN2A, GluN2B, and PSD-95 was assessed by Western blot analysis. Significant genotype × OVX interactions were found for GluN1 and GluN2 expression within the DHP of female mice, suggesting modulation of select NMDA-R levels by female sex hormones is mediated by BDNF. Furthermore, within the DHP BDNF +/− mice show a hypersensitive response to hormone treatment on GluN2 expression which may result from upstream alterations in TrkB phosphorylation. In contrast to the DHP, the VHP showed no effects of hormone manipulation but significant effects of genotype on NMDA-R expression. Castration had no effect on NMDA-R expression; however, androgen treatment had selective effects on GluN2B. These data show case distinct, interactive roles for sex steroid hormones and BDNF in the regulation of NMDA-R expression that are dependent on dorsal versus ventral hippocampal region.
... This result can be duplicated using the ERbeta-specifi c agonist diarylpropionitrile (DPN) but not with the ERalpha-specifi c agonist 4,4',4''-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), suggesting that it is mediated by ERbeta. Subsequent work by this research group confi rmed this in the same model system, showing the absence of effect in hippocampal slices from ERbeta knockout mice (Aguirre et al. 2010 ). In similar studies of hippocampal neuron cultures, a 48 h pretreatment with 17β-estradiol, DPN or PPT was shown to confer protection against glutamate excitotoxicity. ...
Book
Is red wine good for you? And if so, why? How much? And what are the actual benefits? This addition to the SpringerBriefs in Cell Biology series thoroughly but succinctly answers these questions. It covers the biochemistry, health benefits and therapeutic potential of wine grapes. It begins with an overview of phytoalexin production in Vitis vinifera (Common Grape Vine), detailing the relationship of resveratrol to analogues such as pterostilbene, piceid and the viniferins (resveratrol oligomers). The discussion then turns to the hundreds of reports linking resveratrol and related grape vine polyphenols to various beneficial health effects especially cardio- and cerebro- vascular, metabolic, anti-inflammatory and more. Also addressed are the numerous intracellular mechanisms that have been shown to mediate the effects of these compounds in mammalian cells and tissues. Finally, the authors discuss aspects of polyphenol bioavailability and how this will influence choices taken for delivering these compounds as nutritional supplements. A brief chapter containing general conclusions and prospectus rounds out the information.
... Similarly, for 17bE sensitivity experiments, slices were treated with a supraphysiological concentration (100 nM) [28] to help ensure that 17bE-mediated responses were above the limit of detection. For mechanistic studies, glucose was lowered in the presence and absence of 5-aminoimidazole-4carboxamide-1-b-D-ribofuranoside (AICAR; 0.5 mM) [15], Compound C (CC; 10 mM) [15], methylphenolpyrazole (MPP; 10 mM) [29], phenyltrifluoromethylpyrazolophenol (PHTPP; 1 mM) [30], tetrodotoxin (TTX, 500 nM) [22], or tolbutamide (100 mM) [25]. In some cases, glucose was lowered in the presence or absence of the above with and without 17bE (100 nM) or bovine serum albumin-conjugated 17bE (BSA-17bE; 100 nM) [31]. ...
Article
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Objective: Brain regulation of glucose homeostasis is sexually dimorphic; however, the impact sex hormones have on specific neuronal populations within the ventromedial hypothalamic nucleus (VMN), a metabolically sensitive brain region, has yet to be fully characterized. Glucose-excited (GE) and -inhibited (GI) neurons are located throughout the VMN and may play a critical role in glucose and energy homeostasis. Within the ventrolateral portion of the VMN (VL-VMN), glucose sensing neurons and estrogen receptor (ER) distributions overlap. We therefore tested the hypothesis that VL-VMN glucose sensing neurons were sexually dimorphic and regulated by 17β-estradiol (17βE). Methods: Electrophysiological recordings of VL-VMN glucose sensing neurons in brain slices isolated from age- and weight-matched female and male mice were performed in the presence and absence of 17βE. Results: We found a new class of VL-VMN GI neurons whose response to low glucose was transient despite continued exposure to low glucose. Heretofore, we refer to these newly identified VL-VMN GI neurons as ‘adapting’ or AdGI neurons. We found a sexual dimorphic response to low glucose, with male nonadapting GI neurons, but not AdGI neurons, responding more robustly to low glucose than those from females. 17βE blunted the response of both nonadapting GI and AdGI neurons to low glucose in both males and females, which was mediated by activation of estrogen receptor β and inhibition of AMP-activated kinase. In contrast, 17βE had no impact on GE or non-glucose sensing neurons in either sex. Conclusion: These data suggest sex differences and estrogenic regulation of VMN hypothalamic glucose sensing may contribute to the sexual dimorphism in glucose homeostasis.
... Progesterone on its own has neuroprotective properties in vitro (316,455) and in vivo (96,491), while MPA does not (455). Regarding the combined effects of progesterone with estradiol, several studies indicate that progesterone or MPA attenuates the neurotrophic effects of estradiol in vitro and in vivo (6,7,65,95,298,529); but see (382,455). Relative to progesterone, MPA has been found to cause greater attenuation of 17β-estradiol-induced neurotrophic actions (455). ...
Chapter
Sex differences in neurological disease exist in incidence, severity, progression, and symptoms and may ultimately influence treatment. Cognitive disturbances are frequent in neuropsychiatric disease with men showing greater cognitive impairment in schizophrenia, but women showing more severe dementia and cognitive decline with Alzheimer's disease. Although there are no overall differences in intelligence between the sexes, men, and women demonstrate slight but consistent differences in a number of cognitive domains. These include a male advantage, on average, in some types of spatial abilities and a female advantage on some measures of verbal fluency and memory. Sex differences in traits or behaviors generally indicate the involvement of sex hormones, such as androgens and estrogens. We review the literature on whether adult levels of testosterone and estradiol influence spatial ability in both males and females from rodent models to humans. We also include information on estrogens and their ability to modulate verbal memory in men and women. Estrone and progestins are common components of hormone therapies, and we also review the existing literature concerning their effects on cognition. We also review the sex differences in the hippocampus and prefrontal cortex as they relate to cognitive performance in both rodents and humans. There has been greater recognition in the scientific literature that it is important to study both sexes and also to analyze study findings with sex as a variable. Only by examining these sex differences can we progress to finding treatments that will improve the cognitive health of both men and women. © 2016 American Physiological Society. Compr Physiol 6:1295-1337, 2016.
... Postnatal E2 and P4 combined replacement in extremely preterm infants demonstrated reduction of the risk for cerebral palsy, spasticity, and ametropia at 5 years neurodevelopmental follow-up [43]. Several studies have suggested that P4 does not affect the positive effects of E2 [28, 44,45], whereas others proposed that P4 might antagonize the positive effects of E2 [46][47][48][49][50][51]. ...
Article
Full-text available
Estetrol (E4), estradiol (E2) and progesterone (P4) have important antioxidative and neuroprotective effects in neuronal system. We aimed to study the consequence of combined steroid therapy in neonatal hypoxic-ischemic encephalopathy (HIE). In vitro the effect of E4 combined with other steroids on oxidative stress and the cell viability in primary hippocampal cultures was evaluated by lactate dehydrogenase and cell survival assays. In vivo neuroprotective and therapeutic efficacy of E4 combined with other steroids was studied in HIE model of immature rats. The rat pups rectal temperature, body and brain weights were evaluated.The hippocampus and the cortex were investigated by histo/immunohistochemistry: intact cell number counting, expressions of markers for early gray matter lose, neuro- and angiogenesis were studied. Glial fibrillary acidic protein was evaluated by ELISA in blood samples. In vitro E4 and combinations of high doses of E4 with P4 and/or E2 significantly diminished the LDH activity and upregulated the cell survival.In vivopretreatment or treatment by different combinations of E4 with other steroids had unalike effects on body and brain weight, neuro- and angiogenesis, and GFAP expression in blood. The combined use of E4 with other steroids has no benefit over the single use of E4.
... Wbp2 acts as a transcriptional regulator of Esr1 and Pgr (Dhananjayan et al, 2006;Lim et al, 2011). Esr2 expression is linked with Esr1 and Pgr expression (Lindberg et al, 2003;Aguirre et al, 2010). The estrogen receptor ERa (encoded by Esr1) binds to the Shank3 promoter (Kwon et al, 2007), and signalling through the estrogen receptor ERb (encoded by Esr2) increases the levels of Psd-95 and the AMPA receptor component GluR1 (Liu et al, 2008). ...
Article
Full-text available
WBP2 encodes the WW domain-binding protein 2 that acts as a transcriptional coactivator for estrogen receptor α (ESR1) and progesterone receptor (PGR). We reported that the loss of Wbp2 expression leads to progressive high-frequency hearing loss in mouse, as well as in two deaf children, each carrying two different variants in the WBP2 gene. The earliest abnormality we detect in Wbp2-deficient mice is a primary defect at inner hair cell afferent synapses. This study defines a new gene involved in the molecular pathway linking hearing impairment to hormonal signalling and provides new therapeutic targets.
... This result can be duplicated using the ERbeta-specifi c agonist diarylpropionitrile (DPN) but not with the ERalpha-specifi c agonist 4,4',4''-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), suggesting that it is mediated by ERbeta. Subsequent work by this research group confi rmed this in the same model system, showing the absence of effect in hippocampal slices from ERbeta knockout mice (Aguirre et al. 2010 ). In similar studies of hippocampal neuron cultures, a 48 h pretreatment with 17β-estradiol, DPN or PPT was shown to confer protection against glutamate excitotoxicity. ...
Chapter
Full-text available
The cellular mechanisms and proximal targets responsible for resveratrol’s biological activity in mammalian cells are a subject of continued debate amongst the scientific community. One of the earliest activities attributed to resveratrol was that of an estrogen receptor agonist. In this chapter we highlight the striking parallels that exist between the effects elicited by resveratrol and its derivatives, and those associated with estrogen, under a variety of experimental conditions. We discuss other prevalent mechanisms that have been put forward to account for resveratrol’s cellular and systemic effects, including direct interactions with sirtuins, AMPK activation, and phosphodiesterase inhibition. In each instance we relate these mechanisms to estrogen signalling pathways, and build the argument that resveratrol’s properties as an estrogen receptor agonist are central to its biological activities.
... Experiments with PHTPP, indicated that E2mediated neuroprotection against NMDA toxicity was mediated via ERβ receptor (37). Many studies have reported a primary role for ERα as a regulator of the anti-inflammatory properties of estradiol, including the anti-inflammatory and neuroprotective activity of estradiol (38), neuroprotection after ischemia and inhibition of microglial activation (39). Studies involving transgenic mice with targeted deletion of either ERα or Erβ indicate that ERα, but not ERβ, is required for the E2-mediated suppression of BBB permeability (8). ...
Article
Full-text available
Estrogen (E2) has neuroprotective effects on blood-brain-barrier (BBB) after traumatic brain injury (TBI). In order to investigate the roles of estrogen receptors (ERs) in these effects, ER-α antagonist (MPP) and, ER-β antagonist (PHTPP), or non-selective estrogen receptors antagonist (ICI 182780) were administered. Ovariectomized rats were divided into 10 groups, as follows: Sham, TBI, E2, oil, MPP+E2, PHTPP+E2, MPP+PHTPP+E2, ICI+E2, MPP, and DMSO. E2 (33.3 µg/Kg) or oil were administered 30 min after TBI. 1 dose (150 µg/Kg) of each of MPP, PHTPP, and (4 mg/kg) ICI182780 was injected two times, 24 hr apart, before TBI and estrogen treatment. BBB disruption (Evans blue content) and brain edema (brain water content) evaluated 5 hr and 24 hr after the TBI were evaluated, respectively. The results showed that E2 reduced brain edema after TBI compared to vehicle (P<0.01). The brain edema in the MPP+E2 and PHTPP+E2 groups decreased compared to the vehicle (P<0.001). There was no significant difference in MPP+PHTPP+E2 and ICI+E2 compared to TBI. This parameter in MPP was similar to vehicle. Evans blue content in E2 group was lower than vehicle (P<0.05). The inhibitory effect of E2 on Evans blue was not reduced by MPP+E2 and PHTPP+E2 groups, but decreased by treatment with MPP+PHTPP or ICI. MPP had no effect on Evans blue content. A combined administration of MPP and PHTPP or ICI inhibited the E2-induced decrease in brain edema and BBB disruption; this may suggest that these effects were mediated via both receptors.
... However, negative effects of neuroactive steroids have been also reported. One classical example is the effect of PROG on the outcomes of 17b-E neuroprotective actions [109][110][111][112][113]. ...
Article
Evidence accumulated in recent years suggests that the systemic treatment with neuroactive steroids, or the pharmacological modulation of its production by brain cells, represent therapeutic options to promote neuroprotection. However, new findings, which are reviewed in this paper, suggest that the factors to be considered for the design of possible therapies based on neuroactive steroids are more complex than previously thought. Thus, although as recently reported, the nervous system regulates neuroactive steroid synthesis and metabolism in adaptation to modifications in peripheral steroidogenesis, the neuroactive steroid levels in the brain do not fully reflect its levels in plasma. Even, in some cases, neuroactive steroid level modifications occurring in the nervous tissues, under physiological and pathological conditions, are in the opposite direction than in the periphery. This suggests that the systemic treatment with these molecules may have unexpected outcomes on neural steroid levels. In addition, the multiple metabolic pathways and signaling mechanisms of neuroactive steroids, which may change from one brain region to another, together with the existence of regional and sex differences in its neural levels are additional sources of complexity that should be clarified. This complexity in the levels and actions of these molecules may explain why in some cases these molecules have detrimental rather than beneficial actions for the nervous system. This article is part of a Special Issue entitled 'Steroid Perspectives'. Copyright © 2015. Published by Elsevier Ltd.
... It is also important to note that there was also a marked antidepressant-like effect of EB alone in OVX+EB rats (i.e., reduced immobility, increased swimming activity), which was expected but could confound the interpretation of the positive creatine effect observed in the OVX+EB+P females. Fortunately, the inclusion of P-treated groups allowed us to separate out the effects of creatine and EB, as previous work has established that P has inhibitory effects on EB when administered in close proximity (Aguirre et al., 2010;Baudry et al., 2012). Consistent with this literature, antagonistic effects of P on the effects of EB were observed in OVX+EB+P rats across various measures, including forced swimming behaviors, body weights, and mRNA changes. ...
Article
Creatine is an antioxidant, neuromodulator and key regulator of energy metabolism shown to improve depressive symptoms in humans and animals, especially in females. To better understand the pharmacological effects of creatine, we examined its influence on depression-related hippocampal gene expression and behaviors in the presence and absence of sex steroids. Sham-operated and gonadectomized male and female rats were fed chow alone or chow blended with either 2% or 4% w/w creatine monohydrate for five weeks before forced swim, open field, and wire suspension tests, or seven weeks total. Before supplementation, males were chronically implanted with an empty or a testosterone-filled (T) capsule (10-mm surface release), and females were administered progesterone (P, 250 μg), estradiol benzoate (EB, 2.5 μg), EB + P, or sesame oil vehicle weekly. Relative to non-supplemented shams, all hippocampal plasticity-related mRNAs measured, including brain-derived neurotrophic factor (BDNF), tyrosine kinase B, doublecortin, calretinin, and calbindin, were downregulated in sham males given 4% creatine, and BDNF, doublecortin, and calbindin mRNAs were downregulated in sham females given 4% creatine. In contrast, combined 4% creatine + T in castrates prevented downregulation of BDNF, doublecortin, and calretinin mRNAs. Similarly, combined 4% creatine + EB + P in ovariectomized females attenuated downregulation of BDNF and calbindin mRNA levels. Moderate antidepressant and anxiolytic-like behaviors were observed in EB + P-treated ovariectomized females fed creatine, with similar trends in T-treated castrates fed creatine. Altogether, these data show that chronic, high-dose creatine has opposing effects on neuroplasticity-related genes and depressive behavior in intact and gonadectomized male and female rats. The dose and schedule of creatine used negatively impacted hippocampal neuronal integrity in otherwise healthy brains, possibly through negative compensatory changes in energy metabolism, whereas combined creatine and sex steroids acted in a neuroprotective manner in gonadectomized rats, potentially by reducing metabolic complications associated with castration or ovariectomy.
... Although the mechanisms underlying interactions between P 4 and E 2 remain incompletely defined, in vitro and ex vivo studies suggest P 4 may modulate estrogen receptor (ER) expression. In cultured hippocampal slices, E 2 treatment up-regulated ER␤ expression, whereas priming with the P 4 -blocked E 2 induced the up-regulation of ER␤ and inhibited E 2 -mediated neuroprotection (73). In primary hippocampal neuron cultures, P 4 decreased the expression of both ER␣ and ER␤ as well as ER-dependent transcriptional activity (74). ...
Article
Full-text available
Because the estrogen-based hormone therapy (HT) in postmenopausal women typically contains a progestogen component, understanding the interactions between estrogens and progestogens is critical for optimizing the potential neural benefits of HT. An important issue in this regard is the use of continuous versus discontinuous hormone treatments. Although sex steroid hormone levels naturally exhibit cyclic fluctuation, many HT formulations include continuous delivery of hormones. Recent findings from our laboratory and others have shown that co-administration of progesterone (P4) can either attenuate or augment beneficial actions of 17β-estradiol (E2) in experimental models depending in part upon the delivery schedule of P4. In this study, we demonstrate that the P4 delivery schedule in combined E2 and P4 treatments alters degenerative and regenerative outcomes of unilateral entorhinal cortex lesion. We assessed how lesion-induced degeneration of layer II neurons in entorhinal cortex layer and deafferentation in dentate gyrus are affected by ovariectomy and treatments with E2 alone or in combination with either continuous or discontinuous P4. Our results demonstrate the combined efficacy of E2 and P4 is dependent on the administration regimen. Importantly, the discontinuous-combined E2+P4 regimen had the greatest neuroprotective efficacy for both endpoints. These data extend a growing literature that indicates qualitative differences in the neuroprotective effects of E2 as a function of co-treatment with continuous versus discontinuous P4, the understanding of which has important implications for HT in postmenopausal women.
... Indeed, progesterone has significant effects on BDNF-TrkB signalling because studies have shown increases in mRNA and protein expression of BDNF following progesterone treatment, and this was suggested to be mediated via classic progesterone receptors (60). However, other studies have found that progesterone actually inhibits oestrogen-mediated neuroprotection via downregulation of BDNF mRNA in rat hippocampal slices (61). Furthermore, studies in animal models of brain injury have produced conflicting results on the role of BDNF in mediating the protective effects of progesterone (62)(63)(64). ...
Article
Sex steroid hormones and neurotrophic factors are involved in pruning and shaping the developing brain and have been implicated in the pathogenesis of neurodevelopmental disorders. Sex steroid hormones are also involved in the regulation of brain‐derived neurotrophic factor expression. A review of the literature is provided on the relationship between brain‐derived neurotrophic factor and sex steroid hormones, as well as the mechanisms behind this interaction, in the context of how this relationship may be involved in the development of neurodevelopmental psychiatric illnesses, such as schizophrenia and depression.
... Estrogen induced ER-a inhibited excitotoxicity via downregulating calpain expression [41]. In addition, ER-b play an important role in estrogenic neuroprotection against NMDAinduced excitotoxicity [42]. Red ginseng extract was reported to have neuroprotective activity against kainic acid-induced excitotoxicity in vitro and in vivo by inhibition of ROS level [40]. ...
Article
Full-text available
Background Ginseng has been shown to exert anti-stress effects both in vitro and in vivo. However, the effects of ginseng on stress in brain cells are not well understood. In this study, we investigated how Korean Red inseng (KRG) controls hydrogen peroxide-induced apoptosis via regulation of PI3K/AKT and estrogen receptor β signaling. Methods Human neuroblastoma SK-N-SH cells were pre-treated with KRG and subsequently exposed to H2O2. The ability of KRG to inhibit oxidative stress-induced apoptosis was assessed in MTT cytotoxicity assays. Apoptotic protein expression was examined by western blot analysis. The roles of ER-β, PI3K, and p-AKT signaling in KRG regulation of apoptosis were studied using small interfering RNAs and/or target antagonists. Results Pre-treating SK-N-SH cells with KRG decreased expression of the pro-apoptotic proteins p-p53 and caspase-3, but increased expression of the anti-apoptotic protein BCL2. KRG pre-treatment was also associated with increased ERβ, PI3K, and p-AKT expression. Conversely, ER-β inhibition with siRNA or inhibitor treatment increased p-p53 and caspase-3 levels, but decreased BCL2, PI3K, and p-AKT expression. Moreover, inhibition of PI3K/AKT signaling diminished p-p53 and caspase-3 levels, but increased BCL2 expression. Conclusion Collectively, our data indicate that KRG represses oxidative stress-induced apoptosis by enhancing PI3K/AKT signaling via up-regulation of ER-β expression.
... The role of BDNF for behavioral plasticity measures, such as changes in affective or cognitive responding, has been demonstrated in recent reports For example, in an study of anxiety behaviors among female mice over the estrous cycle, genetically manipulated to overexpress a human single nucleotide polymorphism of the BDNF gene associated with anxiety and depression disorders among people, increased anxiety responding over the estrous cycle (Bath et al., 2012). The roles of ovarian steroids, such as estradiol and progesterone, across endogenous cycles, aging, and in animal models of neurodegeneration, for BDNF expression have been described (Bimonte-Nelson et al., 2008;Gibbs, 1998;Meyer et al., 2012); albeit, there is some controversy as to whether progesterone promotes or inhibits estradiol-induced BDNF expression (Aguirre et al., 2010;Aguirre and Baudry, 2009;Bimonte-Nelson et al., 2004;Lorenz et al., 2009;Nilsen and Brinton, 2002;Yao et al., 2011). ...
Article
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Given that the pregnane neurosteroid, 5α-pregnan-3α-ol-20-one (3α,5α-THP), is increased following behavioral challenges (e.g., mating), and that there is behavioral-induced biosynthesis of 3α,5α-THP in midbrain and mesocorticolimbic structures, 3α,5α-THP likely has a role in homeostasis and motivated reproduction and reproduction-related behaviors (e.g., affect, affiliation). The role of pregnane xenobiotic receptor (PXR), involved in cholesterol metabolism, for these effects is of continued interest. We hypothesized that there would be differences in brain levels of 3α,5α-THP following varied behavioral experiences, an effect abrogated by knockdown of PXR in the midbrain. Proestrous rats were infused with PXR antisense oligonucleotides (AS-ODNs) or vehicle to the ventral tegmental area before different behavioral manipulations and assessments. Endpoints were expression levels of PXR in the midbrain, 3α,5α-THP, and ovarian steroids (estradiol, progesterone, dihydroprogesterone) in the midbrain, striatum, hippocampus, hypothalamus, prefrontal cortex, and plasma. Across experiments, knocking down PXR reduced PXR expression and 3α,5α-THP levels in the midbrain and hippocampus. There were differences in terms of the behavioral manipulations, such that paced mating had the most robust effects to increase 3α,5α-THP levels and reduce open field exploration and social interaction. An additional question that was addressed is whether brain-derived neurotrophic factor (BDNF) is a downstream factor for regulating effects of behavioral-induced 3α,5α-THP biosynthesis. Rats infused with PXR AS-ODNs had lower levels of BDNF in the hippocampus. Thus, PXR may be a regulator of mating-induced 3α,5α-THP formation and behavioral changes and neural plasticity, such as BDNF.
... Several biochemical and electrophysiological studies provide evidence that membrane-initiated estradiol signaling regulates female reproductive behaviors by controlling the trafficking neurotransmitter receptors in hypothalamic neurons [2,10]. Estradiol triggered receptor trafficking may also be involved in hippocampal plasticity [46][47][48], and estradiol treatment has been reported to induce pit formation on the membranes of hypothalamic neurons [49,50]. Such pits may represent the fission of endocytotic pits responsible for receptor internalization and fusion exocytotic vesicles delivering ERα to the membrane [42,[49][50][51]. ...
Article
Full-text available
Estradiol is a steroid hormone that binds and activates estradiol receptors. Activation of these receptors is known to modulate neuronal physiology and provide neuroprotection, but it is not completely understood how estradiol mediates these actions on the nervous system. Activation of a sub-population of estradiol receptor-α (ERα), originally identified as a nuclear protein, localizes to the plasma membrane and appears to be a critical step in neuroprotection against brain injury and disease. Previously we showed that estradiol stimulates the rapid and transient trafficking of plasma membrane ERα in primary hypothalamic neurons, and internalization of membrane-impermeant estradiol (E6BSA-FITC) into cortical neuron endosomes in vitro. These findings support the concept that estradiol activates and down-regulates plasma membrane ERα by triggering endocytosis. Here, we use TIRFM (total internal reflection fluorescence microscopy) to image the trafficking of E6BSA-FITC, and GFP-labeled ERα, in live cells in real time. We show that activation of plasma membrane ERs by E6BSA-FITC result in internalization of the fluorescent ligand in live N-38 neurons, an immortalized hypothalamic cell line. Pretreatment with ER antagonist ICI 182,780 decreased the number of E6BSA-FITC labeled puncta observed. We also observed in live N-38 neurons that E6BSA-FITC co-localized with FM4-64 and LysoTracker fluorescent dyes that label endosomes and lysosomes. Our results provide further evidence that plasma membrane ERα activation results in endocytosis of the receptor.
... This result can be duplicated using the ERbeta-specifi c agonist diarylpropionitrile (DPN) but not with the ERalpha-specifi c agonist 4,4',4''-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), suggesting that it is mediated by ERbeta. Subsequent work by this research group confi rmed this in the same model system, showing the absence of effect in hippocampal slices from ERbeta knockout mice (Aguirre et al. 2010 ). In similar studies of hippocampal neuron cultures, a 48 h pretreatment with 17β-estradiol, DPN or PPT was shown to confer protection against glutamate excitotoxicity. ...
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In this chapter we discuss the bioavailability of resveratrol and its related derivatives in red wines. Many of the effects of resveratrol in vitro can be replicated in vivo. However, resveratrol has very low bioavailability and is rapidly metabolized to yield plasma and tissue levels that are several-fold lower than those typically used in experiments with cultured cells. Here we provide an overview of the metabolism of resveratrol in vivo and present data describing its bioavailability in rodents and humans. We discuss some of the strategies that have been used to enhance resveratrol’s uptake and increase its bioavailability, and comment on the possibility that its metabolites share some of resveratrol’s biological activities.
Article
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Historically, progesterone has been studied significantly within the context of reproductive biology. However, there is now an abundance of evidence for its role in regions of the central nervous system (CNS) associated with such non-reproductive functions that include cognition and affect. Here, we describe mechanisms of progesterone action that support its brain-protective effects, and focus particularly on the role of neurotrophins (such as brain-derived neurotrophic factor, BDNF), the receptors that are critical for their regulation, and the role of certain microRNA in influencing the brain-protective effects of progesterone. In addition, we describe evidence to support the particular importance of glia in mediating the neuroprotective effects of progesterone. Through this review of these mechanisms and our own prior published work, we offer insight into why the effects of a progestin on brain protection may be dependent on the type of progestin (e.g., progesterone versus the synthetic, medroxyprogesterone acetate) used, and age, and as such, we offer insight into the future clinical implication of progesterone treatment for such disorders that include Alzheimer’s disease, stroke, and traumatic brain injury.
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Published reports from the CDC’s Autism and Development Disabilities Monitoring Networks have shown that an average of 1 in every 44 (2.3%) 8-year-old children were estimated to have ASD in 2018. Many of the ASDs exhibiting varying degrees of autism-like phenotypes have chromosomal anomalies in the Chr15q11–q13 region. Numerous potential candidate genes linked with ASD reside in this chromosomal segment. However, several clinical, in vivo, and in vitro studies selected one gene more frequently than others randomly and unbiasedly. This gene codes for UBE3A or Ubiquitin protein ligase E3A [also known as E6AP ubiquitin-protein ligase (E6AP)], an enzyme involved in the cellular degradation of proteins. This gene has been listed as one of the several genes with a high potential of causing ASD in the Autism Database. The gain of function mutations, triplication, or duplication in the UBE3A gene is also associated with ASDs like Angelman Syndrome (AS) and Dup15q Syndrome. The genetic imprinting of UBE3A in the brain and a preference for neuronal maternal-specific expression are the key features of various ASDs. Since the UBE3A gene is involved in two main important diseases associated with autism-like symptoms, there has been widespread research going on in understanding the link between this gene and autism. Additionally, since no universal methodology or mechanism exists for identifying UBE3A-mediated ASD, it continues to be challenging for neurobiologists, neuroscientists, and clinicians to design therapies or diagnostic tools. In this review, we focus on the structure and functional aspects of the UBE3A protein, discuss the primary relevance of the 15q11–q13 region in the cause of ASDs, and highlight the link between UBE3A and ASD. We try to broaden the knowledge of our readers by elaborating on the possible mechanisms underlying UBE3A-mediated ASDs, emphasizing the usage of UBE3A as a prospective biomarker in the preclinical diagnosis of ASDs and discuss the positive outcomes, advanced developments, and the hurdles in the field of therapeutic strategies against UBE3A-mediated ASDs. This review is novel as it lays a very detailed and comprehensive platform for one of the most important genes associated with diseases showing autistic-like symptoms. Additionally, this review also attempts to lay optimistic feedback on the possible steps for the diagnosis, prevention, and therapy of these UBE3A-mediated ASDs in the upcoming years.
Article
Neurological disorders are possibly the most prevalent and have been identified to occur among individuals with autism beyond chance. These disorders encompass a diverse range of consequences with neurological causes and have been regarded as a major threat to public mental health. There is no tried-and-true approach for completely protecting the nervous system. Therefore, plant-derived compounds have developed significantly nowadays. Coumestrol (CML) is a potent isoflavone phytoestrogen with a protective effect against neurological dysfunction and has been discovered to be structurally and functionally similar to estrogen. In recent years, more research has been undertaken on phytoestrogens. This research demonstrates the biological complexity of phytoestrogens, which consist of multiple chemical families and function in various ways. This review aimed to explore recent findings on the most significant pharmacological advantages of CML by emphasising neurological benefits. Numerous CML extraction strategies and their pharmacological effects on various neurological disorders, including PD, AD, HD, anxiety, and cognitive impairments, were also documented.
Article
Rats can use several memory systems to navigate a maze toward a reward. Two of these are place memory and response memory and female rats can be biased to predominantly use one over another. Both progesterone and estrogens have been shown to alter memory bias. While the effects of estrogens have been well documented, the effects of progesterone remains somewhat unexplored. Mechanisms through which progesterone may be acting to exert its effects are reviewed here. Converging evidence suggests that the actions of progesterone differ depending on the presence of estrogens, frequently acting in opposition to estrogens when administered together. The hippocampus, dorsal striatum, and prefrontal cortex are likely involved as is the progesterone metabolite, allopregnanolone. There is a need for more research on progesterone and memory bias, especially considering current formulations of hormonal contraceptives include progestins. This article is protected by copyright. All rights reserved.
Article
Autophagy is a protecting intracellular pathway to transmit unnecessary or dysfunctional components to the lysosome for degeneration. Autophagic imbalance is connected with neurodegeneration. Neurodegenerative diseases including Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease are closely related to excitotoxicity and neuronal loss. Activation of G-protein-coupled receptor 30 (GPR30), an estrogen membrane receptor, protects neurons from excitotoxicity-induced cell death. However, whether autophagy is involved in the neuroprotective effect of GPR30 activation is not well known. In this study, methyl thiazolyl tetrazolium (MTT), western blot, monodansylcadaverine (MDC) staining, and immunofluorescent staining were employed to detect the role of autophagy in cultured primary cortical neurons after glutamate exposure and G1 treatment. Pretreatment of G1 (GPR30 specific agonist) reduced neuronal loss through inhibiting excessive autophagy induced by glutamate exposure, which was blocked by GPR30 antagonist G15, phosphatidylinositol-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) inhibitors. These data suggest that GPR30 protects neurons from cell loss primarily by modulating PI3K-AKT-mTOR signaling pathway. In addition, G1 alone did not affect the basal autophagy and cell viability. We conclude that GPR30 activation reduces glutamate-induced excessive autophagy in neurons and protects neurons against excitotoxicity.
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Estrogens play an important role not only in the reproductive system but in the central nervous system as well. Major events of ontogenesis that occur earlier in pregnancy are connected to the formation of estrogen receptors and expression of estrogens leading to the normal physiological development of the central nervous system, though development of the brain by itself is a complex process and lasts during the whole pregnancy. Estetrol (E4) is a recently described natural estrogen with four hydroxyl groups that is synthesized exclusively during pregnancy by the human fetal liver. Its role in the central nervous system is not fully understood. Our studies showed for the first time and proved impressive antioxidative effects of E4 in vitro and proved its tremendous neuroprotective, promyelinating, neurogenic, and cerebro-angiogenic properties in vivo. E4 decreases brain damage markers (S100B and GFAP) in blood assuming that E4 attenuates neonatal hypoxic-ischemic encephalopathy in vivo. We have also shown that the combined use of E4 with other steroids does not have any priority over the single use of E4. E4’s antioxidative actions mostly depend on ERα and ERβ, whereas neurogenesis and possibly promyelinating activities might be realized through ERβ. Taken together our studies suggest importance of E4 treatment possibly not only in neonates but in adults with different neurological diseases like that opening new directions for the use of E4 in clinical practice in neurological diseases.
Article
Objective: In contrast with combined hormonal contraception, progestin-only contraception is not associated with an increase in venous thromboembolism or stroke. Women with migraine are at increased risk of ischaemic stroke. Several studies have reported a reduction in migraine frequency and intensity with desogestrel 75 µg, a progestin-only pill. At present the quality of data is limited by retrospective study designs, lack of control groups and small sample sizes. We present the first prospective nonrandomised controlled trial. Methods: A total of 150 women with migraine visiting our clinic for contraceptive counselling were screened. The intervention group comprised women who opted for contraception with desogestrel (n = 98); the control group comprised women who continued their usual contraceptive (n = 36). Participants completed daily diaries for 90 days before the intervention and 180 days after the intervention. Results: In the intervention group, we found improvements in migraine frequency (p < .001), migraine intensity (p < .001) and the number of triptans used (p < .001). These improvements were already significant after 90 days of desogestrel use (p < .001). Disability scores also decreased significantly. No improvement was seen in the nonintervention group. Conclusion: These data demonstrate for the first time in a prospective controlled setting that daily use of the progestin desogestrel is associated with a decrease in migraine frequency, migraine intensity and pain medication use in women with migraine, with and without aura, who had previously been experiencing at least three days of migraine per month. Trial registration: The study is registered in the University of Zürich database (www.research-projects.uzh.ch/unizh.htm).
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Progestin-only contraception (POC) is not associated with an increased risk for cardiovascular events. In contrast to combined hormonal contraceptives, POC does not increase frequency of migraine attacks and does not initiate migraine. The continuous use of this contraceptive might contribute to the good tolerability in migraineurs. Only for the progestin-only pill with desogestrel 75 μg has it been demonstrated in several studies that it exerts significant reduction in migraine days and migraine intensity. This observation was made for migraine with and without aura. The LNG_IUS 20 is not well tolerated by many migraineurs, potentially as a result of highly fluctuating estrogen levels caused from ovarian cysts.
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Headache during pregnancy can be both primary and secondary and in the last case can be a symptom of a life-threatening condition. Migraine is a risk factor for pregnancy complications, particularly vascular events. It is fundamental looking for the well-known red flags suggesting for a secondary origin of an acute headache during pregnancy. For a differential diagnosis, one or more additional studies can be necessary: brain MRI and MR angiography with contrast, brain CT, ophthalmoscopy, electroencephalography, ultrasound of the vessels of the head and neck, and lumbar puncture. The most common secondary headache is related to preeclampsia, cerebral venous thrombosis (CVT), ischemic or hemorrhagic stroke, subarachnoid hemorrhage (SAH), arterial dissection, reversible cerebral vasoconstriction syndrome (RCVS), posterior reversible leukoencephalopathy syndrome (PRES), idiopathic intracranial hypertension (IIH), and pituitary apoplexy. The preferable management of primary headache during pregnancy and breastfeeding should be non-pharmacological, and only if it is inadequate, the use of medications should be driven by a choice that takes into account all the benefits and possible risks.
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Migraine is three times more prevalent in women than in men [1], with female patients presenting also a higher risk of cardiovascular events, including cardiovascular mortality [2]. Moreover, the intensity and frequency of headaches are higher in women, as well as the risk of chronification, which leads to greater disability [1]. The mechanisms behind the sex disparity in migraine are not completely understood, but it is thought to be mediated through changes in ovarian steroid hormones. Somerville was the first to propose this in the 1970s by studying the effect of estradiol withdrawal in the precipitation of migraine attacks and concluded that during the late luteal phase of the menstrual cycle, the decline in estrogen concentrations in plasma correlates with the precipitation of migraine attacks [3]. This was later confirmed by a recent study that showed that women with migraine present a faster decline in (urinary) estrogen levels during the late luteal phase, compared to controls [4]. Furthermore, during the phases of the menstrual cycle that present elevated levels of estrogen, women appear to have a reduction of migraine attacks, suggesting a protective role [5]. Changes in progesterone, however, do not seem to have a protective nor triggering effect on migraine attacks [6]. The previous results are in line with the occurrence of migraine between sexes during the lifetime. Before puberty, migraine prevalence is similar between sexes and after menarche is increased for women in a 3:1 ratio. Interestingly, similar rates are observed in transsexuals undergoing estrogen therapy for male to female transition [7]. Moreover, not only hormonal changes throughout the menstrual cycle have been seen to alter the frequency of migraine attacks but also fluctuations in hormone levels during pregnancy, puerperium, breastfeeding, perimenopause, and menopause [4, 8, 9]. Disorders such as menorrhagia, dysmenorrhea, polycystic ovary syndrome, and endometriosis have been related to higher prevalence of migraine [10–12]; and, in contrast, the use of hormone replacement therapy, estrogen receptor antagonists, and contraceptive pills seems to reduce the frequency of migraine by reducing hormonal fluctuations [13, 14].
Article
Alzheimer’s disease (AD) is characterised as a provoked inflammatory response and oxidative stress along with amyloid β peptide (Aβ) deposition and neurofibrillary tangles in the brain, and effective treatment is greatly needed. Molecular hydrogen, which has been proposed to be an antioxidant that selectively reduces reactive oxygen species, was found to exert beneficial effects in Aβ injection-induced cognitive dysfunction. However, whether and how hydrogen affects AD pathogenesis remains uninvestigated. Thus, in the present study, APPswe/PS1dE9 (amyloid precursor protein (APP)/PS1) mice, a transgenic AD mouse model, were administered hydrogen-rich water for 3 months and the effects on cognitive function and molecular pathways were investigated. We found that hydrogen-rich water significantly improved cognitive behaviour in female transgenic AD mice without affecting Aβ clearance, and reversed the brain oestrogen level, ERβ, and brain-derived neurotrophic factor (BDNF) expressions that were damaged in female transgenic AD mice, but not in males. Furthermore, hydrogen-rich water ameliorated oxidative stress and inflammatory responses more profoundly in the brains of female AD mice than in those of males. Our results demonstrate a novel sex-specific beneficial effect of hydrogen via oestrogen and brain ERβ-BDNF signalling in AD pathogenesis.
Article
Objectives: There is evidence that men’s perception of contraceptive methods and of their effectiveness and health risks have a major impact on couples contraceptive choices. Engaging men in decision making improves reproductive health outcomes. If they are better informed, men can potentially contribute to more effective use of contraception, thus reducing the rate of sexually transmitted infections and abortion. In Central European countries, few data are available on male contraceptive knowledge and behaviour. Methods: To collect more data we conducted an anonymous survey among young men studying at Zürich University in Switzerland. A questionnaire was distributed to 1500 male students which included a broad range of items addressing sexual behaviour, condom use and knowledge, and attitudes regarding contraceptive methods. Results: Three hundred and sixty-one questionnaires were eligible for evaluation. Condoms and the combined oral contraceptive pill were the most frequently used methods. However, at last intercourse 15.6% of respondents had not used any method of contraception. Many respondents (37%) had had a one-night stand without protection. Contraceptive methods most regarded as unhealthy for women were the combined oral contraceptive pill, progestin-only methods, intrauterine devices (IUDs) and emergency contraception. Characteristics considered by young men to be important in determining contraceptive method choice were: efficacy, partner satisfaction and no impact on fertility and libido. Conclusions: Awareness among male Swiss students about contraceptive methods is high, but in-depth knowledge is limited. Myths were expressed about the combined oral contraceptive pill, progestin-only methods, IUDs and the emergency contraceptive pill. High-risk behaviour occurs frequently. The internet was reported to be the most important source of information about contraception.
Article
Among sex steroid hormones, progesterone and estradiol have a wide diversity of physiological activities that target the nervous system. Not only are they carried by the blood stream, but also they are locally synthesized in the brain and for this reason, estradiol and progesterone are considered 'neurosteroids'. The physiological actions of both hormones range from brain development and neurotransmission to aging, illustrating the importance of a deep understanding of their mechanisms of action. In this review, we summarize key roles that estradiol and progesterone play in the brain. As numerous reports have confirmed a substantial neuroprotective role for estradiol in models of neurodegenerative disease, we focus this review on traumatic brain injury and stroke models. We describe updated data from receptor and signaling events triggered by both hormones, with an emphasis on the mechanisms that have been reported as 'rapid' or 'cytoplasmic actions'. Data showing the therapeutic effects of the hormones, used alone or in combination, are also summarized, with a focus on rodent models of middle cerebral artery occlusion (MCAO). Finally, we draw attention to evidence that neuroprotection by both hormones might be due to a combination of 'cytoplasmic' and 'nuclear' signaling.
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Steroids from the periphery can drive neural functions, but the nervous system is also subject to steroids it produces itself (“neurosteroids”). Neurosteroids can impact sedative/hypnotic behavior, anxiety, cognition, and neuroprotection. At the cellular level, they alter neuronal excitability, synaptic plasticity, and cell proliferation and survival. Early findings promise new therapies for psychological and seizure disorders, neurodegenerative diseases, injuries, and changes related to age. This review summarizes the current state of understanding of neurosteroids and their clinical implications.
Article
Age-related changes in menopausal women put this patient group at an increased risk of fine lines and wrinkles, decreased collagen and elastin, changes to vascularisation, and facial volume loss. Having depleted levels of oestrogen can make it difficult for the skin to retain moisture, resulting in increased dryness, decreased firmness and patchy discolouration. Most women in developed societies can expect to spend at least one-third of their lifetime in the postmenopausal period, when the external signs of ageing can be of the utmost importance to them. Despite this, many aesthetic practitioners may not know the best ways in which to treat these individuals. This paper will explore areas of the face that become more sensitive to hormonal ageing during the perimenopausal, menopausal and postmenopausal periods.
Article
Background: Preclinical evidence suggests that progesterone improves recovery after intracerebral hemorrhage (ICH); however, gonadal hormones have sex-specific effects. Therefore, an experimental model of ICH was used to assess recovery after progesterone administration in male and female rats. Methods: ICH was induced in male and female Wistar rats via stereotactic intrastriatal injection of clostridal collagenase (0.5 U). Animals were randomized to receive vehicle or 8 mg/kg progesterone intraperitoneally at 2 h, then subcutaneously at 5, 24, 48, and 72 h post-injury. Outcomes included relevant physiology during the first 3 h, hemorrhage and edema evolution over the first 24 h, pro-inflammatory transcription factor and cytokine regulation at 24 h, rotarod latency and neuroseverity score over the first 7 days, and microglial activation/macrophage recruitment at 7 days after injury. Results: Rotarod latency (p = 0.001) and neuroseverity score (p = 0.01) were improved in progesterone-treated males, but worsened in progesterone-treated females (p = 0.028 and p = 0.008, respectively). Progesterone decreased cerebral edema (p = 0.04), microglial activation/macrophage recruitment (p < 0.001), and pro-inflammatory transcription factor phosphorylated nuclear factor-kappaB p65 expression (p = 0.0038) in males but not females, independent of tumor necrosis factor-α, interleukin-6, and toll-like receptor-4 expression. Cerebral perfusion was increased in progesterone-treated males at 4 h (p = 0.043) but not 24 h after injury. Hemorrhage volume, arterial blood gases, glucose, and systolic blood pressure were not affected. Conclusions: Progesterone administration improved early neurobehavioral recovery and decreased secondary neuroinflammation after ICH in male rats. Paradoxically, progesterone worsened neurobehavioral recovery and did not modify neuroinflammation in female rats. Future work should isolate mechanisms of sex-specific progesterone effects after ICH.
Article
Epidemiological studies have suggested a differential response, males versus female, in stroke incidence and prognosis. These divergences in brain response after damage are based mostly on hormonal differences. To date, estradiol and progesterone administered independently have demonstrated neuroprotection after ischemia in animal models. Nonetheless, contradictory results were revealed using a combined administration. In order to evaluate the effects of combinatorial treatment administered after ischemia induction, we used two different approaches: in vivo and in vitro models. Male rats which underwent permanent middle cerebral artery occlusion were treated with a combination of estradiol/progesterone at 6, 24 and 48 h after injury and sacrificed at 54 h post-ischemia. The rat brains were evaluated for reactive gliosis, NeuN-positive neurons, levels of synapse-associated proteins and activity levels of PI3K/Akt/GSK3/β-catenin survival pathway. Also, primary cortical neurons were subjected to oxygen and glucose deprivation for 17 h and returned to a normal environment in the presence of estradiol or estradiol/progesterone. Cell viability was evaluated, and activity levels of the PI3K/Akt/GSK3/β-catenin pathway. Our results indicate that some beneficial effects of estradiol were abolished in the presence of progesterone, particularly in the cerebral cortex (core). However, the combinatorial treatment showed positive effects in the hippocampus.
Article
Glutamate is the most abundant excitatory brain neurotransmitter that has important functional significance with respect to neurodegenerative conditions. Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease (AD) has been gradually becoming elucidated recently. Excessive release of glutamate induces an increase in intracellular Ca(2+) levels, thus triggers a cascade of cellular responses, ultimately leading to neuronal cell death. This type of neuronal damage induced by over-excitation has been proposed to be involved in a number of neuropathological conditions, ranging from acute insults to chronic neurodegenerative disorders. Estrogen could be effective in modulating glutamate-induced neurotoxicity and the protective responsivenesses are mostly estrogen receptors (ERs)-dependent. However, the mechanism underlying estrogen's neuroprotective effect is not fully clarified and is complicated by the presence of several distinct ER types. So a deeper research into the neuroprotection of ERs might be informative about the positive effect that estrogen might have on ageing-related cognitive changes. Extensive studies have indicated the neuroprotective effects of ERs against glutamate-induced neurotoxicity. The purpose of this review is to elucidate ERs' neuroprotective effects against glutamate-induced cytotoxicity and explore new ways to prevent and cure neurotoxicity-associated neurodegenerative disorders.
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17β-Estradiol (E2) may influence cognitive and/or affective behavior in part via the β isoform of the estrogen receptor (ERβ). Endocrine status and behavior in cognitive (object recognition, T-maze), anxiety (open field, elevated plus maze, mirror maze, emergence), and motor/coordination (rotarod, activity chamber) tasks of proestrous and diestrous wildtype (WT) and ERβ knockout (βERKO) mice was examined. Proestrous (WT or βERKO), versus diestrous, mice had higher E2 and progestin levels in plasma, hippocampus, and cortex. The only effect of genotype on hormone levels was for corticosterone, such that βERKO mice had higher concentrations of corticosterone than did WT mice. Proestrous WT, but not βERKO, mice had improved performance in the object recognition (greater percentage of time with novel object) and T-maze tasks (greater percentage of spontaneous alternations) and less anxiety-like behavior in the plus maze (increased duration on open arms) and mirror chamber task (increased duration in mirror) than did diestrous mice. This pattern was not seen in the rotarod, open field, or activity monitor, suggesting effects may be specific to affective and cognitive behavior, rather than motor behavior/coordination. Thus, enhanced performance in cognitive tasks and anti-anxiety-like behavior of proestrous mice may require actions of ERβ in the hippocampus and/or cortex.
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Estrogen, in addition to its genomic effects, triggers rapid synaptic changes in hippocampus and cortex. Here we summarize evidence that the acute actions of the steroid arise from actin signaling cascades centrally involved in long-term potentiation (LTP). A 10-min infusion of E2 reversibly increased fast EPSPs and promoted theta burst-induced LTP within adult hippocampal slices. The latter effect reflected a lowered threshold and an elevated ceiling for the potentiation effect. E2's actions on transmission and plasticity were completely blocked by latrunculin, a toxin that prevents actin polymerization. E2 also caused a reversible increase in spine concentrations of filamentous (F-) actin and markedly enhanced polymerization caused by theta burst stimulation (TBS). Estrogen activated the small GTPase RhoA, but not the related GTPase Rac, and phosphorylated (inactivated) synaptic cofilin, an actin severing protein targeted by RhoA. An inhibitor of RhoA kinase (ROCK) thoroughly suppressed the synaptic effects of E2. Collectively, these results indicate that E2 engages a RhoA >ROCK> cofilin> actin pathway also used by brain-derived neurotrophic factor and adenosine, and therefore belongs to a family of 'synaptic modulators' that regulate plasticity. Finally, we describe evidence that the acute signaling cascade is critical to the depression of LTP produced by ovariectomy.
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Following the release of the 2002 report of the Women's Health Initiative (WHI) trial of estrogen plus progestin, the use of menopausal hormone therapy in the United States decreased substantially. Subsequently, the incidence of breast cancer also dropped, suggesting a cause-and-effect relation between hormone treatment and breast cancer. However, the cause of this decrease remains controversial. We analyzed the results of the WHI randomized clinical trial--in which one study group received 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate daily and another group received placebo--and examined temporal trends in breast-cancer diagnoses in the WHI observational-study cohort. Risk factors for breast cancer, frequency of mammography, and time-specific incidence of breast cancer were assessed in relation to combined hormone use. In the clinical trial, there were fewer breast-cancer diagnoses in the group receiving estrogen plus progestin than in the placebo group in the initial 2 years of the study, but the number of diagnoses increased over the course of the 5.6-year intervention period. The elevated risk decreased rapidly after both groups stopped taking the study pills, despite a similar frequency of mammography. In the observational study, the incidence of breast cancer was initially about two times as high in the group receiving menopausal hormones as in the placebo group, but this difference in incidence decreased rapidly in about 2 years, coinciding with year-to-year reductions in combined hormone use. During this period, differences in the frequency of mammography between the two groups were unchanged. The increased risk of breast cancer associated with the use of estrogen plus progestin declined markedly soon after discontinuation of combined hormone therapy and was unrelated to changes in frequency of mammography.
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Estrogens influence the differentiation and maintenance of reproductive tissues and affect lipid metabolism and bone remodeling. Two estrogen receptors (ERs) have been identified to date, ERalpha and ERbeta. We previously generated and studied knockout mice lacking estrogen receptor alpha and reported severe reproductive and behavioral phenotypes including complete infertility of both male and female mice and absence of breast tissue development. Here we describe the generation of mice lacking estrogen receptor beta (ERbeta -/-) by insertion of a neomycin resistance gene into exon 3 of the coding gene by using homologous recombination in embryonic stem cells. Mice lacking this receptor develop normally and are indistinguishable grossly and histologically as young adults from their littermates. RNA analysis and immunocytochemistry show that tissues from ERbeta -/- mice lack normal ERbeta RNA and protein. Breeding experiments with young, sexually mature females show that they are fertile and exhibit normal sexual behavior, but have fewer and smaller litters than wild-type mice. Superovulation experiments indicate that this reduction in fertility is the result of reduced ovarian efficiency. The mutant females have normal breast development and lactate normally. Young, sexually mature male mice show no overt abnormalities and reproduce normally. Older mutant males display signs of prostate and bladder hyperplasia. Our results indicate that ERbeta is essential for normal ovulation efficiency but is not essential for female or male sexual differentiation, fertility, or lactation. Future experiments are required to determine the role of ERbeta in bone and cardiovascular homeostasis.
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Estrogen replacement therapy is associated with improvement of cognitive deficits and reduced incidence of Alzheimer's disease. To compare the impact of therapeutically relevant progestins on estrogen-induced neuroprotection, we treated primary hippocampal neuron cultures with 17beta-E2 and progestin, alone and in combination, 48 h before glutamate insult. Estrogen, progesterone, and 19-norprogesterone, alone or in combination, protected against glutamate toxicity. In contrast, medroxyprogesterone acetate (MPA) failed to protect against glutamate toxicity. Not only was MPA an ineffective neuroprotectant but it attenuated the estrogen- induced neuroprotection when coadministered. We addressed the role of MAPK activation in neuroprotection by ovarian steroids. Estrogen and all three progestins tested, alone or in combination, activated MAPK, indicating another mechanism of protection. Bcl-2 expression has been shown to prevent cell death and is up-regulated by 17beta-E2. Progesterone and 19-norprogesterone, alone or in combination with estrogen, increased Bcl-2 expression. In contrast, MPA blocked estrogen-induced Bcl-2 expression when coadministered. These results may have important implications for the effective use of hormone replacement therapy in the maintenance of neuronal function during menopause and aging and for protection against neurodegenerative diseases such as Alzheimer's disease.
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During development, estrogen has a variety of effects on morphological and electrophysiological properties of hippocampal neurons. Brain-derived neurotrophic factor (BDNF) also plays an important role in the survival and differentiation of neurons during development. We examined the effects of gonadectomy with and without estrogen replacement on the mRNA and protein of BDNF and its receptor, trkB, during early postnatal development of the rat hippocampus. We used immunocytochemistry to demonstrate that estrogen receptor alpha (ERalpha) and BDNF were localized to the same cells within the developing hippocampus. BDNF and ERalpha were colocalized in pyramidal cells of the CA3 subregion and to a lesser extent in CA1. To determine whether BDNF mRNA was regulated by estrogen during development, we gonadectomized male rat pups at postnatal day 0 (P0) and examined mRNA and protein levels from P0 to P25 using real-time reverse transcription-PCR and Western blot analysis. After gonadectomy, BDNF mRNA levels are significantly reduced on P7, but after treatment of gonadectomized animals with estradiol benzoate on P0, levels at all ages were similar to those in intact animals. BDNF mRNA changes after gonadectomy are accompanied by an increase in the levels of BDNF protein, which were reduced by estrogen treatment at P0. We also examined the effect of postnatal estrogen treatment on trkB. There were no significant changes in trkB mRNA or protein in gonadectomized or estrogen-replaced animals. These results suggest that a direct interaction may exist between ERalpha and BDNF to alter hippocampal physiology during development in the rat.
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The central role of glutamate receptors in mediating excitotoxic neuronal death in stroke, epilepsy and trauma has been well established. Glutamate is the major excitatory amino acid transmitter within the CNS and it's signaling is mediated by a number of postsynaptic ionotropic and metabotropic receptors. Although calcium ions are considered key regulators of excitotoxicity, new evidence suggests that specific second messenger pathways rather than total Ca(2+) load, are responsible for mediating neuronal degeneration. Glutamate receptors are found localized at the synapse within electron dense structures known as the postsynaptic density (PSD). Localization at the PSD is mediated by binding of glutamate receptors to submembrane proteins such as actin and PDZ containing proteins. PDZ domains are conserved motifs that mediate protein-protein interactions and self-association. In addition to glutamate receptors PDZ-containing proteins bind a multitude of intracellular signal molecules including nitric oxide synthase. In this way PDZ proteins provide a mechanism for clustering glutamate receptors at the synapse together with their corresponding signal transduction proteins. PSD organization may thus facilitate the individual neurotoxic signal mechanisms downstream of receptors during glutamate overactivity. Evidence exists showing that inhibiting signals downstream of glutamate receptors, such as nitric oxide and PARP-1 can reduce excitotoxic insult. Furthermore we have shown that uncoupling the interaction between specific glutamate receptors from their PDZ proteins protects neurons against glutamate-mediated excitotoxicity. These findings have significant implications for the treatment of neurodegenerative diseases using therapeutics that specifically target intracellular protein-protein interactions.
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose etiology is presently unknown. Probably the most consistent and widespread deficit seen in this syndrome is that of the basal forebrain cholinergic system. We have previously demonstrated that estradiol (E2) modulates the function of these neurons and plays a role in their maintenance by preventing the ovariectomy-induced decrease in choline acetyltransferase activity. It has been postulated that the lack of neurotrophic support may contribute at least in part to degeneration of cholinergic neurons in AD. As such, it is hypothesized that E2 may affect cholinergic function by modulating the levels of certain neurotrophic factors. We have shown that 3 months after ovariectomy (OVX) there was a significant reduction in NGF messenger RNA (mRNA) levels. In the present study, we extended the hypothesis that E2 may serve a neurotrophomodulatory role by assessing the effect of OVX and E2 replacement on brain-derived nerve factor (BDNF) mRN...
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Hippocampal slices prepared from 2-23-day-old neonates were maintained in culture at the interface between air and a culture medium. They were placed on a sterile, transparent and porous membrane and kept in petri dishes in an incubator. No plasma clot or roller drum were used. This method yields thin slices which remain 1-4 cell layers thick and are characterized by a well preserved organotypic organization. Pyramidal neurons labelled by extra- and intracellular application of horse radish peroxidase resemble by the organization and complexity of their dendritic processes those observed in situ at a comparable developmental stage. Excitatory and inhibitory synaptic potentials can easily be analysed using extra- or intracellular recording techniques. After a few days in culture, long-term potentiation of synaptic responses can reproducibly be induced. Evidence for a sprouting response during the first days in culture or following sections is illustrated. This technique may represent an interesting alternative to roller tube cultures for studies of the developmental changes occurring during the first days or weeks in culture.
Article
CONTEXT: Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain. OBJECTIVE: To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States. DESIGN: Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 8.5 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998. INTERVENTIONS: Participants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). MAIN OUTCOMES MEASURES: The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. RESULTS: On May 31, 2002, after a mean of 5.2 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63 (0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes, 0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28) for the global index. Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 person-years. CONCLUSIONS: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.
Article
Estrogen replacement therapy is associated with improvement of cognitive deficits and reduced incidence of Alzheimer's disease. To compare the impact of therapeutically relevant progestins on estrogen-induced neuroprotection, we treated primary hippocampal neuron cultures with 17beta-E2 and progestin, alone and in combination, 48 h before glutamate insult. Estrogen, progesterone, and 19-norprogesterone, alone or in combination, protected against glutamate toxicity. In contrast, medroxyprogesterone acetate (MPA) failed to protect against glutamate toxicity. Not only was MPA an ineffective neuroprotectant but it attenuated the estrogen. induced neuroprotection when coadministered. We addressed the role of MAPK activation in neuroprotection by ovarian steroids. Estrogen and all three progestins tested, alone or in combination, activated MAPK, indicating another mechanism of protection. Bcl-2 expression has been shown to prevent cell death and is up-regulated by 17beta-E2. Progesterone and 19-norprogesterone, alone or in combination with estrogen, increased Bcl-2 expression. In contrast, MPA blocked estrogen-induced Bcl-2 expression when coadministered. These results may have important implications for the effective use of hormone replacement therapy in the maintenance of neuronal function during menopause and aging and for protection against neurodegenerative diseases such as Alzheimer's disease.
Article
Measurement of lactate dehydrogenase (LDH) activity released to the extracellular bathing media has been found to be a simple yet quantitative method for assessing glutamate mediated central neuronal cell injury in cortical cell culture. Extracellular LDH is both chemically and biologically stable; the magnitude of LDH efflux in the cultures correlates in a linear fashion with the number of neurons damaged by glutamate exposure.
Article
Objective: : To update for both clinicians and the lay public the evidence-based position statement published by The North American Menopause Society (NAMS) in March 2007 regarding its recommendations for menopausal hormone therapy (HT) for postmenopausal women, with consideration for the therapeutic benefit-risk ratio at various times through menopause and beyond. Design: : An Advisory Panel of clinicians and researchers expert in the field of women's health was enlisted to review the March 2007 NAMS position statement, evaluate new evidence through an evidence-based analysis, and reach consensus on recommendations. The Panel's recommendations were reviewed and approved by the NAMS Board of Trustees as an official NAMS position statement. The document was provided to other interested organizations to seek their endorsement. Results: : Current evidence supports a consensus regarding the role of HT in postmenopausal women, when potential therapeutic benefits and risks around the time of menopause are considered. This paper lists all these areas along with explanatory comments. Conclusions that vary from the 2007 position statement are highlighted. Addenda include a discussion of risk concepts, a new component not included in the 2007 paper, and a recommended list of areas for future HT research. A suggested reading list of key references is also provided. Conclusions: : Recent data support the initiation of HT around the time of menopause to treat menopause-related symptoms; to treat or reduce the risk of certain disorders, such as osteoporosis or fractures in select postmenopausal women; or both. The benefit-risk ratio for menopausal HT is favorable close to menopause but decreases with aging and with time since menopause in previously untreated women.
Article
This study investigated the expression patterns of estrogen receptor- (ER) and -β (ERβ) in the cultured hippocampal cells of neonatal rats by combined application of cell culture and immunocytochemistry. The results revealed that the expression difference between ER and ERβ seemed to be not obvious in the cultured hippocampal cells of neonatal rats. Moreover, immunoreactivity for either ER or ERβ was observed to be localized in the majority of not only neurons but also astrocytes. The coexpression of both ER and ERβ in the same individual cell was also demonstrated by the double-label immunocytochemistry. Western blot analysis showed that immunoreactivity for ER in the neonatal hippocampal tissues was much higher than in the adult (became rather weak), although there was not such a great difference of immunoreactivity for ERβ. The data also provide direct evidence for the expression of ER subtypes within GABAergic neurons in hippocampal cell cultures and suggest that estrogen's effect on the hippocampus may be mediated at least in part by its ER-containing GABAergic neurons. J. Neurosci. Res. 65:396–402, 2001. © 2001 Wiley-Liss, Inc.
Article
Breast cancer cells show overexpression of estrogen receptor (ER) alpha relative to ERbeta compared to normal breast tissues. This observation has lead to the hypothesis that ERbeta may modulate the proliferative effect of ERalpha. This study investigated how variable cellular expression ratios of the ERalpha and ERbeta modulate the effects on cell proliferation induced by ERalpha or ERbeta agonists, respectively. Using human osteosarcoma (U2OS) ERalpha or ERbeta reporter cells, propyl-pyrazole-triol (PPT) was shown to be a selective ERalpha and diarylpropionitrile (DPN) a preferential ERbeta modulator. The effects of these selective estrogen receptor modulators (SERMs) and of the model compound E2 on the proliferation of T47D human breast cancer cells with tetracycline-dependent expression of ERbeta (T47D-ERbeta) were characterized. E2-induced cell proliferation of cells in which ERbeta expression was inhibited was similar to that of the T47D wild-type cells, whereas this E2-induced cell proliferation was no longer observed when ERbeta expression in the T47D-ERbeta cells was increased. In the T47D-ERbeta cell line, DPN also appeared to be able to suppress cell proliferation when levels of ERbeta expression were high. In the T47D-ERbeta cell line, PPT was unable to suppress cell proliferation at all ratios of ERalpha/ERbeta expression, reflecting its ability to activate only ERalpha and not ERbeta. It is concluded that effects of estrogen-like compounds on cell proliferation are dependent on the actual ERalpha/ERbeta expression levels in these cells or tissues and the potential of the estrogen agonists to activate ERalpha and/or ERbeta.
Article
Due to the many similarities in mechanisms of action, targets and effects, progesterone (P4), estrogen and neurotrophins have been implicated in synaptic plasticity as well as in neuroprotection and neurodegeneration. In this study, we examined the interactions between 17beta-estradiol (E2) and P4 and brain-derived neurotrophic factor (BDNF) on both plasticity and excitotoxicity in rat cultured hippocampal slices. First, we evaluated the neuroprotective effects of E2 and P4 against N-methyl-D-aspartate (NMDA) toxicity in cultured rat hippocampal slices. As previously reported, pretreatment with 10 nm E2 (24 h) was neuroprotective against NMDA toxicity. However, P4 (10 nm) added 20 h after E2 treatment for 4 h reversed its protective effect. In addition, the same E2 treatment resulted in an increase in BDNF protein levels as well as in activation of its receptor, TrkB, while addition of P4 attenuated E2-mediated increase in BDNF and TrkB levels. Furthermore, E2-mediated neuroprotection was eliminated by a BDNF scavenger, TrkB-Fc. Our results indicate that E2 neuroprotective effects are mediated through the BDNF pathway and that, under certain conditions, P4 antagonizes the protective effect of estrogen.
Article
Recent findings indicate that progesterone can attenuate the beneficial neural effects of oestrogen. In the present study, we investigated the hypothesis that progesterone can modulate oestrogen actions by regulating the expression and activity of oestrogen receptors, ERalpha and ERbeta. Our studies in cultured neurones demonstrate that progesterone decreases the expression of both ERalpha and ERbeta and, as a consequence, also reduces both ER-dependent transcriptional activity and neuroprotection. These results identify a potential mechanism by which progesterone antagonises neural oestrogen actions, a finding that may have important implications for hormone therapy in postmenopausal women.
Article
In an attempt to examine regional synthesis of the progesterone receptor (PR) in the brain, the distribution of mRNA encoding PR was investigated in the female adult rat di- and telencephalon by in situ hybridization using T7 RNA polymerase transcripts of a 320 base pair rat PR cDNA clone. The rat PR cDNA had been partially cloned and sequenced by using the reverse transcription-polymerase chain reaction (RT-PCR) method. The primer set corresponds to a part of the progesterone binding domain of human PR cDNA. Large numbers of strong labeling were observed in the arcuate nucleus, medial preoptic nucleus, and ventrolateral part of the ventromedial nucleus which are relative to sexual behavior. Moderate labeling was found in layers II and IV of the isocortex, in the pyramidal layer of the CA1 and CA3 fields of the hippocampal formation, in the cortical nucleus of the amygdala, in the nucleus of the diagonal band, and in the anterior periventricular nucleus. Weak labeling was found in many other regions. These results were largely in agreement with the distribution of PR previously reported by ligand binding assay and autoradiographic studies. This present in situ hybridization study may provide a useful tool for the analysis of the regional regulation of PR synthesis in the rat brain.
Article
Progesterone (P) and 17 beta-estradiol (E) inhibit transcription of alpha mRNA (alpha mRNA) by about 70% in ovine pituitary cultures. In addition, P, but not E, shortens alpha mRNA during the 3-24-h period following treatment. Data presented here focus on this post-transcriptional effect of P, which appears totally independent from transcriptional changes and may alter the translational efficiency of the affected mRNA or its half-life. Results indicate this shortening occurs at the poly(A) tail. The normal length of this tail was estimated to be 70-100 nucleotides in the case of alpha mRNA, and it was shortened by 30-40 nucleotides during P treatment. Shortening was normally observed after 3-10 h of P treatment and was complete by 10-24 h. Significant shortening occurred at 7-10 nM P in ovine pituitary culture; the 10-15-nM concentration of P in the serum of luteal phase ewes also appears sufficient to shorten alpha mRNA in vivo since alpha mRNA from the pituitaries of these ewes was found to be consistently shorter than alpha mRNA from ovariectomized ewes. Finally, P also shortened the poly(A) tail of mRNA for the beta-subunit of LH. This indicates that P-induced poly(A) shortening not only affects alpha mRNA but may affect several or many mRNAs found in ovine gonadotrophs. The significance of poly(A) shortening is not yet understood, but it could involve post-transcriptional inhibition, which, combined with transcriptional effects, may make P a more potent inhibitor of gonadotropin synthesis than E.
Article
Hippocampal slices prepared from 2-23-day-old neonates were maintained in culture at the interface between air and a culture medium. They were placed on a sterile, transparent and porous membrane and kept in petri dishes in an incubator. No plasma clot or roller drum were used. This method yields thin slices which remain 1-4 cell layers thick and are characterized by a well preserved organotypic organization. Pyramidal neurons labelled by extra- and intracellular application of horse radish peroxidase resemble by the organization and complexity of their dendritic processes those observed in situ at a comparable developmental stage. Excitatory and inhibitory synaptic potentials can easily be analysed using extra- or intracellular recording techniques. After a few days in culture, long-term potentiation of synaptic responses can reproducibly be induced. Evidence for a sprouting response during the first days in culture or following sections is illustrated. This technique may represent an interesting alternative to roller tube cultures for studies of the developmental changes occurring during the first days or weeks in culture.
Article
The distribution of cells that express mRNA encoding the androgen (AR) and estrogen (ER) receptors was examined in adult male and female rats by using in situ hybridization. Specific labeling appeared to be largely, if not entirely, localized to neurons. AR and ER mRNA-containing neurons were widely distributed in the rat brain, with the greatest densities of cells in the hypothalamus, and in regions of the telencephalon that provide strong inputs in the medial preoptic and ventromedial nuclei, each of which is thought to play a key role in mediating the hormonal control of copulatory behavior, as well as in the lateral septal nucleus, the medial and cortical nuclei of the amygdala, the amygdalohippocampal area, and the bed nucleus of the stria terminalis. Heavily labeled ER mRNA-containing cells were found in regions known to be involved in the neural control of gonadotropin release, such as the anteroventral periventricular and the arcuate nuclei, but only a moderate density of labeling for AR mRNA was found over these nuclei. In addition, clearly labeled cells were found in regions with widespread connections throughout the brain, including the lateral hypothalamus, intralaminar thalamic nuclei, and deep layers of the cerebral cortex, suggesting that AR and ER may modulate a wide variety of neural functions. Each part of Ammon's horn contained AR mRNA-containing cells, as did both parts of the subiculum, but ER mRNA appeared to be less abundant in the hippocampal formation. Moreover, AR and ER mRNA-containing cells were also found in olfactory regions of the cortex and in both the main and accessory olfactory bulbs. AR and ER may modulate nonolfactory sensory information as well since labeled cells were found in regions involved in the central relay of somatosensory information, including the mesencephalic nucleus of the trigeminal nerve, the ventral thalamic nuclear group, and the dorsal horn of the spinal cord. Furthermore, heavily labeled AR mRNA-containing cells were found in the vestibular nuclei, the cochlear nuclei, the medial geniculate nucleus, and the nucleus of the lateral lemniscus, which suggests that androgens may alter the central relay of vestibular and auditory information as well. However, of all the regions involved in sensory processing, the heaviest labeling for AR and ER mRNA was found in areas that relay visceral sensory information such as the nucleus of the solitary tract, the area postrema, and the subfornical organ. We did not detect ER mRNA in brainstem somatic motoneurons, but clearly labeled AR mRNA-containing cells were found in motor nuclei associated with the fifth, seventh, tenth, and twelfth cranial nerves. Similarly, spinal motoneurons contained AR but not ER mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)
Article
Measurement of lactate dehydrogenase (LDH) activity released to the extracellular bathing media has been found to be a simple yet quantitative method for assessing glutamate mediated central neuronal cell injury in cortical cell culture. Extracellular LDH is both chemically and biologically stable; the magnitude of LDH efflux in the cultures correlates in a linear fashion with the number of neurons damaged by glutamate exposure.
Article
Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose etiology is presently unknown. Probably the most consistent and widespread deficit seen in this syndrome is that of the basal forebrain cholinergic system. We have previously demonstrated that estradiol (E2) modulates the function of these neurons and plays a role in their maintenance by preventing the ovariectomy-induced decrease in choline acetyltransferase activity. It has been postulated that the lack of neurotrophic support may contribute at least in part to degeneration of cholinergic neurons in AD. As such, it is hypothesized that E2 may affect cholinergic function by modulating the levels of certain neurotrophic factors. We have shown that 3 months after ovariectomy (OVX) there was a significant reduction in NGF messenger RNA (mRNA) levels. In the present study, we extended the hypothesis that E2 may serve a neurotrophomodulatory role by assessing the effect of OVX and E2 replacement on brain-derived nerve factor (BDNF) mRNA levels using in situ hybridization. BDNF mRNA levels were quantified in three groups of animals: ovary-intact animals, 28-week ovariectomized (OVX) animals, and E2-replaced OVX animals. Twenty-eight weeks after OVX, there were significant reductions in two of the three cerebral cortical regions analyzed [frontal (35%) and temporal (39%) cortexes], but E2 replacement was without effect. Twenty-eight weeks after OVX, there were also reductions in BDNF mRNA in all subregions of the hippocampus except CA1 (CA2 by 38%, CA3 by 44%, CA4 by 39%, and dentate gyrus by 37%), whereas E2 replacement was effective in elevating BDNF mRNA levels in the CA3, CA4, and dentate gyrus subregions. Collectively, the data demonstrate that E2 deprivation leads to a reduction in BDNF mRNA. Further, at the time point studied, E2 replacement is more effective in maintaining BDNF mRNA in the hippocampus than in the cortex, suggesting a regional difference in the ovarian steroid requirement for expression of BDNF.
Article
Changes in membrane potentials were recorded from rat hippocampal slices with a voltage-sensitive dye using a real-time optical recording system, which had high spatial resolution of 128 x 128 points with a high time resolution of 0.6 ms. Serial excitatory propagation was recorded in the dentate gyrus. CA3 and CA1 after stimulation of the perforant pathway, and the optical signals were clearly divided into two components in the dentate gyrus adjacent to the stimulus site. The slow component was suppressed in Ca(2+)-free solution, but the fast component in the molecular layer was not affected. However, the application of 1 microM tetrodotoxin fully abolished both components. These results suggest that the fast and slow components mainly reflect Na(+)-dependent action potentials and excitatory postsynaptic potentials, respectively. The excitatory response duration in the stratum radiatum of CA3 was significantly longer than that in other hippocampal areas. The long-lasting excitation in CA3 is probably related to the CA3 associational projections, because direct stimulation of CA3 pyramidal cell layer also produced similar results. The long-lasting dendritic excitation is probably important to integrate synaptic transmission and may be related to epileptogenesis. When long-term potentiation was induced by a tetanic stimulation (100 Hz for 1 s), the onset latency in the stratum radiatum of CA1 was reduced to as much as 65%, suggesting an increase of excitatory propagation. The analysis of the spatial-temporal optical signals contributes to understanding information processes in the hippocampus, related to learning and memory including long-term potentiation.
Article
Alzheimer's disease affects women more often than men, and women with this form of dementia show greater naming (semantic memory) deficits during the course of their illness. Gonadal steroids exert organizational and activational effects on central nervous system neurons and influence brain function in other important ways. Several estrogenic actions are potentially relevant to Alzheimer's disease, and it is hypothesized that one consequence of estrogen deprivation after the menopause is a higher risk of this dementing disorder. In healthy women without dementia, estrogen may enhance cognitive performance, especially in the domain of verbal memory, although the magnitude of such effects is small. Several small treatment trials of estrogen replacement in women with Alzheimer's disease, however, suggest that estrogen's effects on cognition could be larger in this population and may be most apparent on tasks of semantic memory. Analyses in voluntary cohorts associate postmenopausal estrogen replacement therapy with a lower risk of subsequent Alzheimer's disease. In 3 recent epidemiologic studies, information on postmenopausal estrogen use was collected prospectively; while inconclusive, findings raise the possibility that postmenopausal estrogen replacement reduces a woman's risk of subsequent dementia. New information from basic research and from large randomized treatment studies, cohort studies, and case-control studies is needed to resolve important unanswered clinical issues.
Article
Estrogen plays a profound role in regulating the structure and function of many neuronal systems in the adult rat brain. The actions of estrogen were thought to be mediated by a single nuclear estrogen receptor (ER) until the recent cloning of a novel ER (ER-beta). To ascertain which ER is involved in the regulation of different brain regions, the present study compared the distribution of the classical (ER-alpha) and novel (ER-beta) forms of ER mRNA-expressing neurons in the central nervous system (CNS) of the rat with in situ hybridization histochemistry. Female rat brain, spinal cord, and eyes were frozen, and cryostat sections were collected on slides, hybridized with [35S]-labeled antisense riboprobes complimentary to ER-alpha or ER-beta mRNA, stringently washed, and opposed to emulsion. The results of these studies revealed the presence of ER-alpha and ER-beta mRNA throughout the rostral-caudal extent of the brain and spinal cord. Neurons of the olfactory bulb, supraoptic, paraventricular, suprachiasmatic, and tuberal hypothalamic nuclei, zona incerta, ventral tegmental area, cerebellum (Purkinje cells), laminae III-V, VIII, and IX of the spinal cord, and pineal gland contained exclusively ER-beta mRNA. In contrast, only ER-alpha hybridization signal was seen in the ventromedial hypothalamic nucleus and subfornical organ. Perikarya in other brain regions, including the bed nucleus of the stria terminalis, medial and cortical amygdaloid nuclei, preoptic area, lateral habenula, periaqueductal gray, parabrachial nucleus, locus ceruleus, nucleus of the solitary tract, spinal trigeminal nucleus and superficial laminae of the spinal cord, contained both forms of ER mRNA. Although the cerebral cortex and hippocampus contained both ER mRNAs, the hybridization signal for ER-alpha mRNA was very weak compared with ER-beta mRNA. The results of these in situ hybridization studies provide detailed information about the distribution of ER-alpha and ER-beta mRNAs in the rat CNS. In addition, this comparative study provides evidence that the region-specific expression of ER-alpha, ER-beta, or both may be important in determining the physiological responses of neuronal populations to estrogen action.
Article
Findings from basic neuroscience have elucidated mechanisms of action of estrogen on the structure and function of brain areas known to be critically involved in memory. Controlled clinical studies of the administration of estrogen to postmenopausal women have found that estrogen enhances verbal memory and maintains the ability to learn new material. These findings are supported by those from investigations of healthy, elderly, women and by results of a study in which younger women received a gonadotropin releasing-hormone analog that suppressed ovarian function. The specificity of the estrogenic effect on cognitive functions is consistent with known sex differences in cognitive abilities and suggests that, in adulthood, estrogen serves to activate neural pathways established under the influence of this steroid hormone during prenatal life.
Article
Recent studies suggest that hormone replacement therapy can help to reduce the risk and severity of Alzheimer's-related dementia in postmenopausal women. We have hypothesized that these effects are due, in part, to the ability for estrogen and progesterone to enhance hippocampal function, as well as the functional status of cholinergic projections to the hippocampus and cortex, by influencing the expression of specific neurotrophins and neurotrophin receptors. In the present study, quantitative in situ hybridization techniques were used to determine whether the levels of trkA mRNA in the basal forebrain, and nerve growth factor (NGF) mRNA and brain-derived neurotrophic factor (BDNF) mRNA in the hippocampus, are significantly affected by physiological changes in circulating gonadal steroids. Gonadally intact animals were sacrificed at different stages of the estrous cycle and ovariectomized animals were sacrificed at different times following the administration of either estrogen or estrogen plus progesterone. In gonadally intact animals, significant fluctuations in the levels of trkA mRNA in the medial septum (MS), and BDNF mRNA in regions CA1 and CA3/4 of the hippocampus, were detected across the estrous cycle. In animals that received hormone replacement, a significant increase (30.4%) in trkA mRNA was detected in the MS of animals sacrificed 24 h following estrogen administration. Levels of trkA mRNA in the MS declined to control levels over the next 48 h; however, a single injection of progesterone administered 48 h after estradiol appeared to prevent any further decline in trkA mRNA over the next 24 h. In addition, significant increases in BDNF mRNA were detected in the dentate granule cell layer (73.4%), region CA1 (28. 1%), and region CA3/4 (76.9%) of animals sacrificed 53 h after receiving estrogen and 5 h after receiving progesterone. No significant changes in trkA mRNA were detected in the nucleus basalis magnocellularis, and no significant changes in NGF mRNA were detected in the hippocampus. These data demonstrate that levels of trkA mRNA in the MS, and BDNF mRNA in the hippocampus, are affected by physiological changes in the levels of circulating gonadal steroids and are elevated in response to acute hormone replacement. The relevance of these effects to the ability for estrogen replacement to enhance cholinergic activity and hippocampal function, and thereby reduce the risk and severity of Alzheimer's-related dementia in postmenopausal women, is discussed.
Article
The benefits and risks of hormone replacement therapy (HRT) in postmenopausal women are not fully defined, and individual characteristics and preferences may influence decisions to use this therapy. Previous studies of postmenopausal women who use HRT have been conducted in local or highly selected cohorts or have not focused on current use. To examine sociodemographic, clinical, and psychological factors associated with current use of HRT in a national population-based cohort. Random-digit telephone survey. Probability sample of U.S. households with a telephone. 495 postmenopausal women 50 to 74 years of age in 1995. Current use of HRT. Current use of HRT was reported by 37.6% of women (58.7% of those who underwent hysterectomy and 19.6% of those who did not undergo hysterectomy; P = 0.001). In multivariable analyses, use of HRT was more common among women in the South (adjusted odds ratio, 2.67 [95% CI, 1.08 to 6.59]) and West (odds ratio, 2.76 [CI, 1.01 to 7.53]) than the Northeast. Use was more common among college graduates (odds ratio, 3.72 [CI, 1.29 to 10.71]) and less common among women with diabetes mellitus (odds ratio, 0.17 [CI, 0.05 to 0.51]). Other cardiac risk factors and most psychological characteristics were not associated with HRT use. Sociodemographic factors, such as region and education, may be more strongly associated with use of HRT than clinical factors, such as risk for cardiovascular disease. Future efforts should focus on understanding sociodemographic variations, defining which women are most likely to benefit, and targeting therapy to them.
Article
Estrogen receptors are direct regulators of transcription that function by binding to specific DNA sequences in promoters of target genes. The two cloned forms of estrogen receptors, alpha and beta, are expressed in the central nervous system by different neuronal populations. Astrocytes in vitro are also reported to express estrogen receptor alpha; however, this expression has not been confirmed in the rat brain in vivo. The apparent absence of estrogen receptors in glia in vivo contrasts with the well-known effects of this hormone on astrocytes of different brain areas, including the hippocampal formation. In this study, the expression of estrogen receptors in the hippocampal formation of adult male rats has been assessed by confocal microscopy. Estrogen receptor alpha-immunoreactivity was localized in neuronal nuclei in the pyramidal cell layer of CA1-CA3 fields. Estrogen receptor beta-immunoreactivity was observed in the perikarya, apical dendrites, and cell nuclei of pyramidal neurons in CA1 and CA2. Furthermore, estrogen receptor beta-immunoreactive glia were observed in CA1, CA2, CA3, and in the hilus of the dentate gyrus of male and female rats. Estrogen receptor beta-immunoreactivity was localized in glial processes and perikarya and, in some cases, in glial cell nuclei. Double immunocytochemical labeling of estrogen receptor beta and the specific astroglial marker glial fibrillary acidic protein revealed that estrogen receptor beta-immunoreactive glial cells were astrocytes. Estrogen receptor alpha was not co-localized with glial fibrillary acidic protein. The presence of estrogen receptor beta in astrocytes of adult male and female rats demonstrates a possible mechanism by which estrogen can directly modulate gene expression in these cells.