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Branigan GL, Torrandell-Haro G, Chen S, Shang Y, Perez-Miller S, Mao Z, Padilla-Rodriguez M, Cortes-Flores H, Vitali F, Brinton RD. Breast cancer therapies reduce risk of Alzheimer's disease and promote estrogenic pathways and action in brain. iScience 2023; 26:108316. [PMID: 38026173 PMCID: PMC10663748 DOI: 10.1016/j.isci.2023.108316] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 09/08/2023] [Accepted: 10/20/2023] [Indexed: 12/01/2023] Open
Abstract
Worldwide, an ever-increasing number of women are prescribed estrogen-modulating therapies (EMTs) for the treatment of breast cancer. In parallel, aging of the global population of women will contribute to risk of both breast cancer and Alzheimer's disease. To address the impact of anti-estrogen therapies on risk of Alzheimer's and neural function, we conducted medical informatic and molecular pharmacology analyses to determine the impact of EMTs on risk of Alzheimer's followed by determination of EMT estrogenic mechanisms of action in neurons. Collectively, these data provide both clinical and mechanistic data indicating that select EMTs exert estrogenic agonist action in neural tissue that are associated with reduced risk of Alzheimer's disease while simultaneously acting as effective estrogen receptor antagonists in breast.
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Affiliation(s)
- Gregory L. Branigan
- Center for Innovation in Brain Science, University of Arizona; Tucson AZ, USA
- Department of Pharmacology, University of Arizona College of Medicine; Tucson AZ, USA
- Medical Scientist Training Program, University of Arizona College of Medicine; Tucson AZ, USA
| | - Georgina Torrandell-Haro
- Center for Innovation in Brain Science, University of Arizona; Tucson AZ, USA
- Department of Pharmacology, University of Arizona College of Medicine; Tucson AZ, USA
| | - Shuhua Chen
- Center for Innovation in Brain Science, University of Arizona; Tucson AZ, USA
| | - Yuan Shang
- Center for Innovation in Brain Science, University of Arizona; Tucson AZ, USA
| | | | - Zisu Mao
- Center for Innovation in Brain Science, University of Arizona; Tucson AZ, USA
| | | | | | - Francesca Vitali
- Center for Innovation in Brain Science, University of Arizona; Tucson AZ, USA
- Center of Bioinformatics and Biostatistics, University of Arizona College of Medicine; Tucson AZ, USA
| | - Roberta Diaz Brinton
- Center for Innovation in Brain Science, University of Arizona; Tucson AZ, USA
- Department of Pharmacology, University of Arizona College of Medicine; Tucson AZ, USA
- Department of Neurology, University of Arizona College of Medicine; Tucson AZ, USA
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Daniel JM, Lindsey SH, Mostany R, Schrader LA, Zsombok A. Cardiometabolic health, menopausal estrogen therapy and the brain: How effects of estrogens diverge in healthy and unhealthy preclinical models of aging. Front Neuroendocrinol 2023; 70:101068. [PMID: 37061205 PMCID: PMC10725785 DOI: 10.1016/j.yfrne.2023.101068] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/23/2023] [Accepted: 04/10/2023] [Indexed: 04/17/2023]
Abstract
Research in preclinical models indicates that estrogens are neuroprotective and positively impact cognitive aging. However, clinical data are equivocal as to the benefits of menopausal estrogen therapy to the brain and cognition. Pre-existing cardiometabolic disease may modulate mechanisms by which estrogens act, potentially reducing or reversing protections they provide against cognitive decline. In the current review we propose mechanisms by which cardiometabolic disease may alter estrogen effects, including both alterations in actions directly on brain memory systems and actions on cardiometabolic systems, which in turn impact brain memory systems. Consideration of mechanisms by which estrogen administration can exert differential effects dependent upon health phenotype is consistent with the move towards precision or personalized medicine, which aims to determine which treatment interventions will work for which individuals. Understanding effects of estrogens in both healthy and unhealthy models of aging is critical to optimizing the translational link between preclinical and clinical research.
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Affiliation(s)
- Jill M Daniel
- Department of Psychology and Brain Institute, Tulane University, New Orleans, LA, United States.
| | - Sarah H Lindsey
- Department of Pharmacology and Brain Institute, Tulane University, New Orleans, LA, United States
| | - Ricardo Mostany
- Department of Pharmacology and Brain Institute, Tulane University, New Orleans, LA, United States
| | - Laura A Schrader
- Department of Cell & Molecular Biology and Brain Institute, Tulane University, New Orleans, LA, United States
| | - Andrea Zsombok
- Department of Physiology and Brain Institute, Tulane University, New Orleans, LA, United States
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Kommaddi RP, Verma A, Muniz-Terrera G, Tiwari V, Chithanathan K, Diwakar L, Gowaikar R, Karunakaran S, Malo PK, Graff-Radford NR, Day GS, Laske C, Vöglein J, Nübling G, Ikeuchi T, Kasuga K, Ravindranath V. Sex difference in evolution of cognitive decline: studies on mouse model and the Dominantly Inherited Alzheimer Network cohort. Transl Psychiatry 2023; 13:123. [PMID: 37045867 PMCID: PMC10097702 DOI: 10.1038/s41398-023-02411-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 03/15/2023] [Accepted: 03/24/2023] [Indexed: 04/14/2023] Open
Abstract
Women carry a higher burden of Alzheimer's disease (AD) compared to men, which is not accounted entirely by differences in lifespan. To identify the mechanisms underlying this effect, we investigated sex-specific differences in the progression of familial AD in humans and in APPswe/PS1ΔE9 mice. Activity dependent protein translation and associative learning and memory deficits were examined in APPswe/PS1ΔE9 mice and wild-type mice. As a human comparator group, progression of cognitive dysfunction was assessed in mutation carriers and non-carriers from DIAN (Dominantly Inherited Alzheimer Network) cohort. Female APPswe/PS1ΔE9 mice did not show recall deficits after contextual fear conditioning until 8 months of age. Further, activity dependent protein translation and Akt1-mTOR signaling at the synapse were impaired in male but not in female mice until 8 months of age. Ovariectomized APPswe/PS1ΔE9 mice displayed recall deficits at 4 months of age and these were sustained until 8 months of age. Moreover, activity dependent protein translation was also impaired in 4 months old ovariectomized APPswe/PS1ΔE9 mice compared with sham female APPswe/PS1ΔE9 mice. Progression of memory impairment differed between men and women in the DIAN cohort as analyzed using linear mixed effects model, wherein men showed steeper cognitive decline irrespective of the age of entry in the study, while women showed significantly greater performance and slower decline in immediate recall (LOGIMEM) and delayed recall (MEMUNITS) than men. However, when the performance of men and women in several cognitive tasks (such as Wechsler's logical memory) are compared with the estimated year from expected symptom onset (EYO) we found no significant differences between men and women. We conclude that in familial AD patients and mouse models, females are protected, and the onset of disease is delayed as long as estrogen levels are intact.
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Affiliation(s)
- Reddy Peera Kommaddi
- Centre for Brain Research, Indian Institute of Science, Bangalore, 560012, India.
| | - Aditi Verma
- Centre for Neuroscience, Indian Institute of Science, Bangalore, 560012, India
| | - Graciela Muniz-Terrera
- Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, Scotland, UK
- The Department of Social Medicine, Ohio University, Athens, OH, 45701, USA
| | - Vivek Tiwari
- Centre for Brain Research, Indian Institute of Science, Bangalore, 560012, India
| | | | - Latha Diwakar
- Centre for Brain Research, Indian Institute of Science, Bangalore, 560012, India
| | - Ruturaj Gowaikar
- Centre for Neuroscience, Indian Institute of Science, Bangalore, 560012, India
| | - Smitha Karunakaran
- Centre for Neuroscience, Indian Institute of Science, Bangalore, 560012, India
| | - Palash Kumar Malo
- Centre for Brain Research, Indian Institute of Science, Bangalore, 560012, India
| | - Neill R Graff-Radford
- Department of Neurology, Mayo Clinic Florida, Mayo Clinic College of Medicine and Science, 4500 San Pablo Road S, Jacksonville, FL, 32224, USA
| | - Gregory S Day
- Department of Neurology, Mayo Clinic Florida, Mayo Clinic College of Medicine and Science, 4500 San Pablo Road S, Jacksonville, FL, 32224, USA
| | - Christoph Laske
- German Center for Neurodegenerative Diseases, Munich, Germany
- Section for Dementia Research, Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
| | - Jonathan Vöglein
- Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
| | - Georg Nübling
- Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
- German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
| | - Takeshi Ikeuchi
- Department of Molecular Genetics, Center for Bioresources, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8585, Japan
| | - Kensaku Kasuga
- Department of Molecular Genetics, Center for Bioresources, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata, 951-8585, Japan
| | - Vijayalakshmi Ravindranath
- Centre for Brain Research, Indian Institute of Science, Bangalore, 560012, India
- Centre for Neuroscience, Indian Institute of Science, Bangalore, 560012, India
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Mucci V, Demori I, Browne CJ, Deblieck C, Burlando B. Fibromyalgia in Pregnancy: Neuro-Endocrine Fluctuations Provide Insight into Pathophysiology and Neuromodulation Treatment. Biomedicines 2023; 11:biomedicines11020615. [PMID: 36831148 PMCID: PMC9953487 DOI: 10.3390/biomedicines11020615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 02/06/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Fibromyalgia (FM) is a chronic pain disorder with unclear pathophysiological mechanisms, which leads to challenges in patient management. In addition to pain, the disorder presents with a broad range of symptoms, such as sleep disruption, chronic fatigue, brain fog, depression, muscle stiffness, and migraine. FM has a considerable female prevalence, and it has been shown that symptoms are influenced by the menstrual cycle and periods of significant hormonal and immunological changes. There is increasing evidence that females with FM experience an aggravation of symptoms in pregnancy, particularly during the third trimester and after childbirth. In this perspective paper, we focus on the neuro-endocrine interactions that occur between progesterone, allopregnanolone, and cortisol during pregnancy, and propose that they align with our previously proposed model of FM pathogenesis based on GABAergic "weakening" in a thalamocortical neural loop system. Based on our hypothesis, we introduce the possibility of utilizing transcranial direct current stimulation (tDCS) as a non-invasive treatment potentially capable of exerting sex-specific effects on FM patients.
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Affiliation(s)
- Viviana Mucci
- School of Science, Western Sydney University, Campbelltown, NSW 2560, Australia
- Correspondence:
| | - Ilaria Demori
- Department of Earth, Environmental and Life Sciences (DISTAV), University of Genova, Corso Europa, 26, 16132 Genova, Italy
| | - Cherylea J. Browne
- School of Science, Western Sydney University, Campbelltown, NSW 2560, Australia
- Translational Neuroscience Facility, School of Medical Sciences, UNSW Sydney, Kensington, NSW 2052, Australia
- Brain Stimulation and Rehabilitation (BrainStAR) Lab, School of Health Sciences, Western Sydney University, Campbelltown, NSW 2560, Australia
| | - Choi Deblieck
- Antwerp Management School, University of Antwerp, Boogkeers 5, 2000 Antwerp, Belgium
| | - Bruno Burlando
- Department of Pharmacy, DIFAR, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy
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Li XT. The modulation of potassium channels by estrogens facilitates neuroprotection. Front Cell Dev Biol 2022; 10:998009. [PMID: 36393851 PMCID: PMC9643774 DOI: 10.3389/fcell.2022.998009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 10/11/2022] [Indexed: 08/31/2023] Open
Abstract
Estrogens, the sex hormones, have the potential to govern multiple cellular functions, such as proliferation, apoptosis, differentiation, and homeostasis, and to exert numerous beneficial influences for the cardiovascular system, nervous system, and bones in genomic and/or non-genomic ways. Converging evidence indicates that estrogens serve a crucial role in counteracting neurodegeneration and ischemic injury; they are thereby being considered as a potent neuroprotectant for preventing neurological diseases such as Alzheimer's disease and stroke. The underlying mechanism of neuroprotective effects conferred by estrogens is thought to be complex and multifactorial, and it remains obscure. It is well established that the K+ channels broadly expressed in a variety of neural subtypes determine the essential physiological features of neuronal excitability, and dysfunction of these channels is closely associated with diverse brain deficits, such as ataxia and epilepsy. A growing body of evidence supports a neuroprotective role of K+ channels in malfunctions of nervous tissues, with the channels even being a therapeutic target in clinical trials. As multitarget steroid hormones, estrogens also regulate the activity of distinct K+ channels to generate varying biological actions, and accumulated data delineate that some aspects of estrogen-mediated neuroprotection may arise from the impact on multiple K+ channels, including Kv, BK, KATP, and K2P channels. The response of these K+ channels after acute or chronic exposure to estrogens may oppose pathological abnormality in nervous cells, which serves to extend our understanding of these phenomena.
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Affiliation(s)
- Xian-Tao Li
- School of Medicine, Guizhou University, Guiyang, China
- Department of Neuroscience, South-Central University for Nationalities, Wuhan, China
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Andrews EJ, Martini AC, Head E. Exploring the role of sex differences in Alzheimer's disease pathogenesis in Down syndrome. Front Neurosci 2022; 16:954999. [PMID: 36033603 PMCID: PMC9411995 DOI: 10.3389/fnins.2022.954999] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 07/25/2022] [Indexed: 11/14/2022] Open
Abstract
Women are disproportionately affected by Alzheimer's disease (AD), yet little is known about sex-specific effects on the development of AD in the Down syndrome (DS) population. DS is caused by a full or partial triplication of chromosome 21, which harbors the amyloid precursor protein (APP) gene, among others. The majority of people with DS in their early- to mid-40s will accumulate sufficient amyloid-beta (Aβ) in their brains along with neurofibrillary tangles (NFT) for a neuropathological diagnosis of AD, and the triplication of the APP gene is regarded as the main cause. Studies addressing sex differences with age and impact on dementia in people with DS are inconsistent. However, women with DS experience earlier age of onset of menopause, marked by a drop in estrogen, than women without DS. This review focuses on key sex differences observed with age and AD in people with DS and a discussion of possible underlying mechanisms that could be driving or protecting from AD development in DS. Understanding how biological sex influences the brain will lead to development of dedicated therapeutics and interventions to improve the quality of life for people with DS and AD.
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Affiliation(s)
- Elizabeth J. Andrews
- Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, United States
| | - Alessandra C. Martini
- Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, United States
| | - Elizabeth Head
- Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, United States
- Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, United States
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Buggio L, Barbara G, Facchin F, Ghezzi L, Dridi D, Vercellini P. The influence of hormonal contraception on depression and female sexuality: a narrative review of the literature. Gynecol Endocrinol 2022; 38:193-201. [PMID: 34913798 DOI: 10.1080/09513590.2021.2016693] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVE Over the past decades, an increasing number of women have been using hormonal contraception. The potential role of sex hormones in regulating vegetative, psychophysiological, and cognitive functions has been highlighted in several studies, and there is a need to further understand the impact of hormonal contraception on women's quality of life, especially as regards psychological health and sexuality. METHODS We conducted a narrative review aimed at clarifying the mechanisms involved in the interaction between sex hormones and the brain, also focusing on the association between hormonal contraception and mood and sexual function. RESULTS Our findings clarified that hormonal contraception may be associated with depressive symptoms, especially among adolescents, and with sexual dysfunction. However, the evidence included in this review was conflicting and did not support the hypothesis that hormonal contraception directly causes depressive symptoms, major depressive disorder, or sexual dysfunction. CONCLUSIONS The optimal hormonal contraception should be identified in the context of shared decision making, considering the preferences and needs of each woman, as well as her physical and psychosexual conditions.
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Affiliation(s)
- Laura Buggio
- Gynecology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giussy Barbara
- Gynecology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- SVSeD, Service for Sexual and Domestic Violence and Obstetric and Gynecology Emergency Department, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Commenda, Italy
- Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, Milan, Italy
| | - Federica Facchin
- Department of Psychology, Catholic University of the Sacred Heart, Milan, Italy
| | - Laura Ghezzi
- Department of Neurology, Washington University, St. Louis, MO, USA
- Dino Ferrari Center, Università degli Studi di Milano, Milan, Italy
| | - Dhouha Dridi
- Gynecology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Paolo Vercellini
- Gynecology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, Milan, Italy
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8
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An P, Zhao XC, Liu MJ, You YQ, Li JY. Gender-based differences in neuroprotective effects of hydrogen gas against intracerebral hemorrhage-induced depression. Neurochem Int 2022; 153:105276. [PMID: 34995727 DOI: 10.1016/j.neuint.2022.105276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 12/31/2021] [Accepted: 01/02/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND Post-stroke depression (PSD) severely affects recovery in patients with intracerebral hemorrhage (ICH). Although hydrogen gas (H2) exerts excellent neuroprotective effects in patients with ICH, there are sex-based differences in H2 efficacy in several diseases. Herein, we determined whether estrogen increases susceptibility to the neuroprotective effects of H2 in males with ICH-induced depression. METHODS A rodent model of ICH in the basal ganglia was established using autologous blood injection (30 μL). Mice were treated with 2.9% H2 for 2 h daily for 3 days post-ICH. Estrogen (1 mg/kg) was administered by subcutaneous injection daily for 3 days to male mice post-ICH. Thirty days post-ICH, PSD was evaluated by sucrose preference, forced swimming, and 3-chamber social tests. Following the completion of behavioral tests, levels of superoxide dismutase (SOD) and reactive oxygen species (ROS), astrocytic activation, phosphorylated (p)-NF-κB-positive astrocytes, p-NF-κB, p-IKKβ, IL-1β, and IL-6 expression were determined. RESULTS Compared with female mice, H2 administration post-ICH exhibited fewer neuroprotective effects, including decreased sucrose consumption and time spent sniffing a novel mouse, increased immobility time, downregulated total SOD content, upregulated ROS content and p-NF-κB levels, and elevated astrocyte branches, whereas estrogen enhanced the neuroprotective effects of H2 in male mice. A reduced number of p-NF-κB-positive astrocytes, downregulated expression of p-NF-κB, p-IKKβ, IL-1β, and IL-6 in the amygdala were demonstrated in ICH-males treated with estrogen plus H2. CONCLUSIONS Estrogen was responsible for increased H2 sensitivity in male mice with ICH. The underlying mechanism may be associated with the suppression of NF-κB signaling in astrocytes.
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Affiliation(s)
- Ping An
- Department of Neurobiology, School of Life Science, China Medical University, Shenyang, People's Republic of China.
| | - Xiao-Chun Zhao
- Department of Anesthesiology, School and Hospital of Stomatology, China Medical University, Shenyang, People's Republic of China.
| | - Man-Jia Liu
- Department of Anesthesiology, ShengJing Hospital of China Medical University, Shenyang, People's Republic of China.
| | - Yu-Qing You
- Department of Anesthesiology, ShengJing Hospital of China Medical University, Shenyang, People's Republic of China.
| | - Jing-Ya Li
- Department of Anesthesiology, ShengJing Hospital of China Medical University, Shenyang, People's Republic of China.
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Conde DM, Verdade RC, Valadares ALR, Mella LFB, Pedro AO, Costa-Paiva L. Menopause and cognitive impairment: A narrative review of current knowledge. World J Psychiatry 2021; 11:412-428. [PMID: 34513605 PMCID: PMC8394691 DOI: 10.5498/wjp.v11.i8.412] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 07/05/2021] [Accepted: 07/28/2021] [Indexed: 02/06/2023] Open
Abstract
A severe impairment of cognitive function characterizes dementia. Mild cognitive impairment represents a transition between normal cognition and dementia. The frequency of cognitive changes is higher in women than in men. Based on this fact, hormonal factors likely contribute to cognitive decline. In this sense, cognitive complaints are more common near menopause, a phase marked by a decrease in hormone levels, especially estrogen. Additionally, a tendency toward worsened cognitive performance has been reported in women during menopause. Vasomotor symptoms (hot flashes, sweating, and dizziness), vaginal dryness, irritability and forgetfulness are common and associated with a progressive decrease in ovarian function and a subsequent reduction in the serum estrogen concentration. Hormone therapy (HT), based on estrogen with or without progestogen, is the treatment of choice to relieve menopausal symptoms. The studies conducted to date have reported conflicting results regarding the effects of HT on cognition. This article reviews the main aspects of menopause and cognition, including the neuroprotective role of estrogen and the relationship between menopausal symptoms and cognitive function. We present and discuss the findings of the central observational and interventional studies on HT and cognition.
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Affiliation(s)
- Délio Marques Conde
- Department of Gynecology and Obstetrics, Federal University of Goiás, Goiânia 74605-050, Goiás, Brazil
| | - Roberto Carmignani Verdade
- Department of Obstetrics and Gynecology, School of Medical Sciences, State University of Campinas, Campinas 13083-881, São Paulo, Brazil
| | - Ana L R Valadares
- Department of Obstetrics and Gynecology, School of Medical Sciences, State University of Campinas, Campinas 13083-881, São Paulo, Brazil
| | - Lucas F B Mella
- Department of Medical Psychology and Psychiatry-Geriatric Psychiatry and Neuropsychiatric Division, State University of Campinas, Campinas 13083-887, São Paulo, Brazil
| | - Adriana Orcesi Pedro
- Department of Obstetrics and Gynecology, School of Medical Sciences, State University of Campinas, Campinas 13083-881, São Paulo, Brazil
| | - Lucia Costa-Paiva
- Department of Obstetrics and Gynecology, School of Medical Sciences, State University of Campinas, Campinas 13083-881, São Paulo, Brazil
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Abotalebi H, Ebrahimi B, Shahriyari R, Shafieian R. Sex steroids-induced neurogenesis in adult brain: a better look at mechanisms and mediators. Horm Mol Biol Clin Investig 2021; 42:209-221. [PMID: 34058796 DOI: 10.1515/hmbci-2020-0036] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 01/14/2021] [Indexed: 11/15/2022]
Abstract
Adult neurogenesis is the production of new nerve cells in the adult brain. Neurogenesis is a clear example of the neuroplasticity phenomenon which can be observed in most of mammalian species, including human beings. This phenomenon occurs, at least, in two regions of the brain: the subgranular zone of the dentate gyrus in hippocampus and the ventricular zone of lateral ventricles. Numerous studies have investigated the relationship between sex steroid hormones and neurogenesis of adult brain; of which, mostly concentrated on the role of estradiol. It has been shown that estrogen plays a significant role in this process through both classic and non-classic mechanisms, including a variety of different growth factors. Therefore, the objective of this review is to investigate the role of female sex steroids with an emphasis on estradiol and also its potential implications for regulating the neurogenesis in the adult brain.
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Affiliation(s)
- Hamideh Abotalebi
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Babak Ebrahimi
- Department of Anatomy and Cell Biology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Raziyeh Shahriyari
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reyhaneh Shafieian
- Department of Anatomy and Cell Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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11
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Means JC, Lopez AA, Koulen P. Estrogen Protects Optic Nerve Head Astrocytes Against Oxidative Stress by Preventing Caspase-3 Activation, Tau Dephosphorylation at Ser 422 and the Formation of Tau Protein Aggregates. Cell Mol Neurobiol 2021; 41:449-458. [PMID: 32385548 PMCID: PMC7648721 DOI: 10.1007/s10571-020-00859-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 04/28/2020] [Indexed: 12/15/2022]
Abstract
Glaucoma is a neurodegenerative disorder that leads to the slow degeneration of retinal ganglion cells, and results in damage to the optic nerve and concomitant vision loss. As in other disorders affecting the viability of central nervous system neurons, neurons affected by glaucoma do not have the ability to regenerate after injury. Recent studies indicate a critical role for optic nerve head astrocytes (ONHAs) in this process of retinal ganglion cell degeneration. Cleavage of tau, a microtubule stabilizing protein and constituent of neurofibrillary tangles (NFT), plays a major part in the mechanisms that lead to toxicity in CNS neurons and astrocytes. Here, we tested the hypothesis that estrogen, a pleiotropic neuro- and cytoprotectant with high efficacy in the CNS, prevents tau cleavage, and hence, protects ONHAs against cell damage caused by oxidative stress. Our results indicate that estrogen prevents caspase-3 mediated tau cleavage, and thereby decreases the levels of the resulting form of proteolytically cleaved tau protein, which leads to a decrease in NFT formation, which requires proteolytically cleaved tau protein. Overall, our data propose that by stopping the reduction of estrogen levels involved with aging the sensitivity of the optic nerve to glaucomatous damage might be reduced. Furthermore, our data suggest that therapeutic use of estrogen may be beneficial in slowing or preventing the onset or severity of neurodegenerative diseases such as glaucoma and potentially also other degenerative diseases of the CNS through direct control of posttranslational modifications of tau protein.
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Affiliation(s)
- John C Means
- Department of Ophthalmology, School of Medicine, Vision Research Center, University of Missouri - Kansas City, 2411 Holmes St., Kansas City, MO, 64108, USA
| | - Adam A Lopez
- Department of Ophthalmology, School of Medicine, Vision Research Center, University of Missouri - Kansas City, 2411 Holmes St., Kansas City, MO, 64108, USA
| | - Peter Koulen
- Department of Ophthalmology, School of Medicine, Vision Research Center, University of Missouri - Kansas City, 2411 Holmes St., Kansas City, MO, 64108, USA.
- Department of Biomedical Sciences, School of Medicine, University of Missouri - Kansas City, 2411 Holmes St., Kansas City, MO, USA.
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Impact of quercetin on tight junctional proteins and BDNF signaling molecules in hippocampus of PCBs-exposed rats. Interdiscip Toxicol 2019; 11:294-305. [PMID: 31762681 PMCID: PMC6853011 DOI: 10.2478/intox-2018-0029] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Accepted: 02/06/2018] [Indexed: 12/26/2022] Open
Abstract
Polychlorinated biphenyls (PCBs) consist of a range of toxic substances which are directly proportional to carcinogenesis and tumor-promoting factors as well as having neurotoxic properties. Reactive oxygen species, which are produced from PCBs, alter blood–brain barrier (BBB) integrity, which is paralleled by cytoskeletal rearrangements and redistribution and disappearance of tight junction proteins (TJPs) like claudin-5 and occludin. Brain-derived neurotrophic factor (BDNF), plays an important role in the maintenance, survival of neurons and synaptic plasticity. It is predominant in the hippocampal areas vital to learning, memory and higher thinking. Quercetin, a flavonoid, had drawn attention to its neurodefensive property. The study is to assess the role of quercetin on serum PCB, estradiol and testosterone levels and mRNA expressions of estrogen receptor α and β, TJPs and BDNF signaling molecules on the hippocampus of PCBs-exposed rats. Rats were divided into 4 groups of 6 each. Group I rats were intraperitoneally (i.p.) administered corn oil (vehicle). Group II received quercetin 50 mg/kg/bwt (gavage). Group III received PCBs (Aroclor 1254) at 2 mg/kg bwt (i.p). Group IV received quercetin 50 mg/kg bwt (gavage) simultaneously with PCBs 2 mg/kg bwt (i.p.). The treatment was given daily for 30 days. The rats were euthanized 24 h after the experimental period. Blood was collected for quantification of serum PCBs estradiol and testosterone. The hippocampus was dissected and processed for PCR and Western blot; serum PCB was observed in PCB treated animals, simultaneously quercetin treated animals showed PCB metabolites. Serum testosterone and estradiol were decreased after PCB exposure. Quercetin supplementation brought back normal levels. mRNA expressions of estrogen α and β were decreased in the hippocampus of PCB treated rats. TJPS and BDNF signalling molecules were decreased in hippocampus of PCB treated rats. Quercetin supplementation retrieved all the parameters. Quercetin alone treated animals showed no alteration. Thus in PCB caused neurotoxicity, quercetin protects and prevents neuronal damage in the hippocampus.
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Mohajeri M, Martín-Jiménez C, Barreto GE, Sahebkar A. Effects of estrogens and androgens on mitochondria under normal and pathological conditions. Prog Neurobiol 2019; 176:54-72. [DOI: 10.1016/j.pneurobio.2019.03.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 02/23/2019] [Accepted: 03/05/2019] [Indexed: 02/06/2023]
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Pottoo FH, Javed MN, Barkat MA, Alam MS, Nowshehri JA, Alshayban DM, Ansari MA. Estrogen and Serotonin: Complexity of Interactions and Implications for Epileptic Seizures and Epileptogenesis. Curr Neuropharmacol 2019; 17:214-231. [PMID: 29956631 PMCID: PMC6425080 DOI: 10.2174/1570159x16666180628164432] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Revised: 02/01/2018] [Accepted: 06/25/2018] [Indexed: 12/15/2022] Open
Abstract
A burgeoning literature documents the confluence of ovarian steroids and central serotonergic systems in the injunction of epileptic seizures and epileptogenesis. Estrogen administration in animals reduces neuronal death from seizures by up-regulation of the prosurvival molecule i.e. Bcl-2, anti-oxidant potential and protection of NPY interneurons. Serotonin modulates epileptiform activity in either direction i.e administration of 5-HT agonists or reuptake inhibitors leads to the activation of 5-HT3 and 5-HT1A receptors tending to impede focal and generalized seizures, while depletion of brain 5-HT along with the destruction of serotonergic terminals leads to expanded neuronal excitability hence abatement of seizure threshold in experimental animal models. Serotonergic neurotransmission is influenced by the organizational activity of steroid hormones in the growing brain and the actuation effects of steroids which come in adulthood. It is further established that ovarian steroids bring induction of dendritic spine proliferation on serotonin neurons thus thawing a profound effect on serotonergic transmission. This review features 5-HT1A and 5-HT3 receptors as potential targets for ameliorating seizure-induced neurodegeneration and recurrent hypersynchronous neuronal activity. Indeed 5-HT3 receptors mediate cross-talk between estrogenic and serotonergic pathways, and could be well exploited for combinatorial drug therapy against epileptogenesis.
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Affiliation(s)
- Faheem Hyder Pottoo
- Address correspondence to these authors at the Department of Epidemic Disease Research, Institute of Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University (Formerly University of Dammam), Dammam 31441, Saudi Arabia; E-mail: and Department of Pharmacology, College of Clinical Pharmacy, 31441 Imam Abdulrahman Bin Faisal University, (Formerly University of Dammam), Dammam, Saudi Arabia; E-mail:
| | | | | | | | | | | | - Mohammad Azam Ansari
- Address correspondence to these authors at the Department of Epidemic Disease Research, Institute of Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University (Formerly University of Dammam), Dammam 31441, Saudi Arabia; E-mail: and Department of Pharmacology, College of Clinical Pharmacy, 31441 Imam Abdulrahman Bin Faisal University, (Formerly University of Dammam), Dammam, Saudi Arabia; E-mail:
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Hanson AM, Perera KLIS, Kim J, Pandey RK, Sweeney N, Lu X, Imhoff A, Mackinnon AC, Wargolet AJ, Van Hart RM, Frick KM, Donaldson WA, Sem DS. A-C Estrogens as Potent and Selective Estrogen Receptor-Beta Agonists (SERBAs) to Enhance Memory Consolidation under Low-Estrogen Conditions. J Med Chem 2018; 61:4720-4738. [PMID: 29741891 DOI: 10.1021/acs.jmedchem.7b01601] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Estrogen receptor-beta (ERβ) is a drug target for memory consolidation in postmenopausal women. Herein is reported a series of potent and selective ERβ agonists (SERBAs) with in vivo efficacy that are A-C estrogens, lacking the B and D estrogen rings. The most potent and selective A-C estrogen is selective for activating ER relative to seven other nuclear hormone receptors, with a surprising 750-fold selectivity for the β over α isoform and with EC50s of 20-30 nM in cell-based and direct binding assays. Comparison of potency in different assays suggests that the ER isoform selectivity is related to the compound's ability to drive the productive conformational change needed to activate transcription. The compound also shows in vivo efficacy after microinfusion into the dorsal hippocampus and after intraperitoneal injection (0.5 mg/kg) or oral gavage (0.5 mg/kg). This simple yet novel A-C estrogen is selective, brain penetrant, and facilitates memory consolidation.
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Affiliation(s)
- Alicia M Hanson
- Department of Pharmaceutical Sciences, Center for Structure-Based Drug Design and Development , Concordia University Wisconsin , Mequon , Wisconsin 53097 , United States
| | - K L Iresha Sampathi Perera
- Department of Chemistry , Marquette University , P.O. Box 1881, Milwaukee , Wisconsin 53201-1881 , United States
| | - Jaekyoon Kim
- Department of Psychology , University of Wisconsin-Milwaukee , 2441 East Hartford Avenue , Milwaukee , Wisconsin 53211 , United States
| | - Rajesh K Pandey
- Department of Chemistry , Marquette University , P.O. Box 1881, Milwaukee , Wisconsin 53201-1881 , United States
| | - Noreena Sweeney
- Department of Pharmaceutical Sciences, Center for Structure-Based Drug Design and Development , Concordia University Wisconsin , Mequon , Wisconsin 53097 , United States
| | - Xingyun Lu
- Department of Pharmaceutical Sciences, Center for Structure-Based Drug Design and Development , Concordia University Wisconsin , Mequon , Wisconsin 53097 , United States
| | - Andrea Imhoff
- Department of Pharmaceutical Sciences, Center for Structure-Based Drug Design and Development , Concordia University Wisconsin , Mequon , Wisconsin 53097 , United States
| | - Alexander Craig Mackinnon
- Department of Pathology , Medical College of Wisconsin , 9200 West Wisconsin Avenue , Milwaukee , Wisconsin 53226 , United States
| | - Adam J Wargolet
- Department of Natural Science , Concordia University Wisconsin , Mequon , Wisconsin 53097 , United States
| | - Rochelle M Van Hart
- Department of Natural Science , Concordia University Wisconsin , Mequon , Wisconsin 53097 , United States
| | - Karyn M Frick
- Department of Psychology , University of Wisconsin-Milwaukee , 2441 East Hartford Avenue , Milwaukee , Wisconsin 53211 , United States
| | - William A Donaldson
- Department of Chemistry , Marquette University , P.O. Box 1881, Milwaukee , Wisconsin 53201-1881 , United States
| | - Daniel S Sem
- Department of Pharmaceutical Sciences, Center for Structure-Based Drug Design and Development , Concordia University Wisconsin , Mequon , Wisconsin 53097 , United States
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Tenkorang MA, Snyder B, Cunningham RL. Sex-related differences in oxidative stress and neurodegeneration. Steroids 2018; 133:21-27. [PMID: 29274405 PMCID: PMC5864532 DOI: 10.1016/j.steroids.2017.12.010] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 12/13/2017] [Accepted: 12/18/2017] [Indexed: 02/07/2023]
Abstract
Oxidative stress has been implicated in a number of neurodegenerative diseases spanning various fields of research. Reactive oxygen species can be beneficial or harmful, depending on their concentration. High levels of reactive oxygen species can lead to oxidative stress, which is an imbalance between free radicals and antioxidants. Increased oxidative stress can result in cell loss. Interestingly, sex differences have been observed in oxidative stress generation, which may underlie sex differences observed in neurodegenerative disorders. An enhanced knowledge of the role of sex hormones on oxidative stress signaling and cell loss can yield valuable information, leading to sex-based mechanistic approaches to neurodegeneration.
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Affiliation(s)
- Mavis A Tenkorang
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Brina Snyder
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Rebecca L Cunningham
- Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, United States.
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17
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Engler-Chiurazzi EB, Brown CM, Povroznik JM, Simpkins JW. Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury. Prog Neurobiol 2017; 157:188-211. [PMID: 26891883 PMCID: PMC4985492 DOI: 10.1016/j.pneurobio.2015.12.008] [Citation(s) in RCA: 146] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 11/06/2015] [Accepted: 12/10/2015] [Indexed: 12/30/2022]
Abstract
There is ample empirical evidence to support the notion that the biological impacts of estrogen extend beyond the gonads to other bodily systems, including the brain and behavior. Converging preclinical findings have indicated a neuroprotective role for estrogen in a variety of experimental models of cognitive function and brain insult. However, the surprising null or even detrimental findings of several large clinical trials evaluating the ability of estrogen-containing hormone treatments to protect against age-related brain changes and insults, including cognitive aging and brain injury, led to hesitation by both clinicians and patients in the use of exogenous estrogenic treatments for nervous system outcomes. That estrogen-containing therapies are used by tens of millions of women for a variety of health-related applications across the lifespan has made identifying conditions under which benefits with estrogen treatment will be realized an important public health issue. Here we provide a summary of the biological actions of estrogen and estrogen-containing formulations in the context of aging, cognition, stroke, and traumatic brain injury. We have devoted special attention to highlighting the notion that estrogen appears to be a conditional neuroprotectant whose efficacy is modulated by several interacting factors. By developing criteria standards for desired beneficial peripheral and neuroprotective outcomes among unique patient populations, we can optimize estrogen treatments for attenuating the consequences of, and perhaps even preventing, cognitive aging and brain injury.
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Affiliation(s)
- E B Engler-Chiurazzi
- Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV 26506, United States; Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV 26506, United States.
| | - C M Brown
- Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV 26506, United States; Department of Neurobiology and Anatomy, West Virginia University, Morgantown, WV 26506, United States.
| | - J M Povroznik
- Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV 26506, United States; Department of Pediatrics, West Virginia University, Morgantown, WV 26506, United States.
| | - J W Simpkins
- Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV 26506, United States; Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV 26506, United States.
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Coman L, Păunescu H, Catană R, Coman LI, Voiculescu Ş, Coman OA. ALZHEIMER'S DISEASE - ESTROGENS AND SELECTIVE ESTROGEN RECEPTOR MODULATORS, FRIENDS OR FOES? ACTA ENDOCRINOLOGICA-BUCHAREST 2017; 13:77-83. [PMID: 31149152 DOI: 10.4183/aeb.2017.77] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Alzheimer's disease(AD) is the leading cause of dementia and is characterized by the presence of extensive plaque deposition and neurofibrillary pathology. The aim of the present study was to make an update regarding the influence of estrogens and SERMs on inflammation and on the resolution of inflammation, respectively, focusing on these most important features implicated in the pathophysiology of AD. Several hypothesised mechanisms of action of estrogens and SERM are exposed and also some relevant clinical studies on this subject are analysed. The analyzed studies have a high heterogeneity of preparations used, of administration routes, of the female population included and of the periods of time from the appearance/induction of menopause to the therapeutic intervention and also of follow-up periods of patients and of the means of evaluating their cognitive decline. One can say that all the ways of pharmacological influence on the membrane or intracellular signalling system associated to estrogens that may have clinical importance in the prevention and possibly in the treatment of AD have not been exhausted. Estrogens with selective ERα or G protein-coupled estrogen receptors (GPER1 or GqMER) effects could be used to influence the resolution of inflammation process, with positive effects on AD evolution.
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Affiliation(s)
- L Coman
- "Carol Davila" University of Medicine and Pharmacy, Faculty of Pharmacy, Dept. of Physiology, Bucharest, Romania
| | - H Păunescu
- "Carol Davila" University of Medicine and Pharmacy, Faculty of Pharmacy, Dept. of Pharmacology and Pharmacotherapy, Bucharest, Romania
| | - R Catană
- "Carol Davila" University of Medicine and Pharmacy, Faculty of Pharmacy, Dept. of Pathophysiology and Immunology, Bucharest, Romania
| | - L I Coman
- "Carol Davila" University of Medicine and Pharmacy, Faculty of Pharmacy, Student, Bucharest, Romania
| | - Ş Voiculescu
- "Carol Davila" University of Medicine and Pharmacy, Faculty of Pharmacy, Dept. of Surgery, Bucharest, Romania
| | - O A Coman
- "Carol Davila" University of Medicine and Pharmacy, Faculty of Pharmacy, Dept. of Pharmacology and Pharmacotherapy, Bucharest, Romania
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19
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Bethea CL, Reddy AP, Christian FL. How Studies of the Serotonin System in Macaque Models of Menopause Relate to Alzheimer's Disease1. J Alzheimers Dis 2017; 57:1001-1015. [PMID: 27662311 PMCID: PMC5575917 DOI: 10.3233/jad-160601] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Serotonin plays a key role in mood or affect, and dysfunction of the serotonin system has been linked to depression in humans and animal models. Depression appears prior to or coincident with overt symptoms of Alzheimer's disease (AD) in about 50% of patients, and some experts consider it a risk factor for the development of AD. In addition, AD is more prevalent in women, who also show increased incidence of depression. Indeed, it has been proposed that mechanisms underlying depression overlap the mechanisms thought to hasten AD. Women undergo ovarian failure and cessation of ovarian steroid production in middle age and the postmenopausal period correlates with an increase in the onset of depression and AD. This laboratory has examined the many actions of ovarian steroids in the serotonin system of non-human primates using a rhesus macaque model of surgical menopause with short or long-term estradiol (E) or estradiol plus progesterone (E+P) replacement therapy. In this mini-review, we present a brief synopsis of the relevant literature concerning AD, depression, and serotonin. We also present some of our data on serotonin neuron viability, the involvement of the caspase-independent pathway, and apoptosis-inducing factor in serotonin-neuron viability, as well as gene expression related to neurodegeneration and neuron viability in serotonin neurons from adult and aged surgical menopausal macaques. We show that ovarian steroids, particularly E, are crucial for serotonin neuron function and health. In the absence of E, serotonin neurons are endangered and deteriorating toward apoptosis. The possibility that this scenario may proceed or accompany AD in postmenopausal women seems likely.
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Affiliation(s)
- Cynthia L Bethea
- Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Beaverton, OR 97229 and Department of Obstetrics and Gynecology, Oregon Health and Sciences University, Portland, OR 97239
| | - Arubala P Reddy
- Department of Internal Medicine, Texas Tech Health Science Center, Lubbock, Texas 79430
| | - Fernanda Lima Christian
- Federal University of Santa Catarina, Center of Biological Sciences, Department of Physiological Sciences, Florianópolis, SC - Brazil 88040-900
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20
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Marriott L, Wenk G. Neurobiological Consequences of Long-Term Estrogen Therapy. CURRENT DIRECTIONS IN PSYCHOLOGICAL SCIENCE 2016. [DOI: 10.1111/j.0963-7214.2004.00301.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Postmenopausal women demonstrate an increased incidence of Alzheimer's disease (AD). Epidemiological evidence suggests that estrogen replacement therapy (ERT) may reduce the risk or delay the onset of AD, yet recent clinical trials found no cognitive benefits of ERT in women with mild to moderate AD. This review suggests that the timing of estrogen administration may explain these conflicting results. Chronic administration has neurobiological consequences that can affect neural and immune function, but a therapy designed to mimic the natural cycle of fluctuating hormones may more effectively slow the progression of AD in postmenopausal women.
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Affiliation(s)
- L.K. Marriott
- Division of Neural Systems, Memory & Aging, Arizona Research Laboratories, University of Arizona
| | - G.L. Wenk
- Division of Neural Systems, Memory & Aging, Arizona Research Laboratories, University of Arizona
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21
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Hamson DK, Roes MM, Galea LAM. Sex Hormones and Cognition: Neuroendocrine Influences on Memory and Learning. Compr Physiol 2016; 6:1295-337. [DOI: 10.1002/cphy.c150031] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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22
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Frick KM. Molecular mechanisms underlying the memory-enhancing effects of estradiol. Horm Behav 2015; 74:4-18. [PMID: 25960081 PMCID: PMC4573242 DOI: 10.1016/j.yhbeh.2015.05.001] [Citation(s) in RCA: 130] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Revised: 04/25/2015] [Accepted: 05/01/2015] [Indexed: 11/18/2022]
Abstract
This article is part of a Special Issue "Estradiol and cognition". Since the publication of the 1998 special issue of Hormones and Behavior on estrogens and cognition, substantial progress has been made towards understanding the molecular mechanisms through which 17β-estradiol (E2) regulates hippocampal plasticity and memory. Recent research has demonstrated that rapid effects of E2 on hippocampal cell signaling, epigenetic processes, and local protein synthesis are necessary for E2 to facilitate the consolidation of object recognition and spatial memories in ovariectomized female rodents. These effects appear to be mediated by non-classical actions of the intracellular estrogen receptors ERα and ERβ, and possibly by membrane-bound ERs such as the G-protein-coupled estrogen receptor (GPER). New findings also suggest a key role of hippocampally-synthesized E2 in regulating hippocampal memory formation. The present review discusses these findings in detail and suggests avenues for future study.
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Affiliation(s)
- Karyn M Frick
- Department of Psychology, University of Wisconsin-Milwaukee, 2441 E. Hartford Ave., Milwaukee, WI 53211, USA.
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23
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Mannella P, Simoncini T, Genazzani AR. Estrogens and progestins: molecular effects on brain cells. Horm Mol Biol Clin Investig 2015; 4:609-13. [PMID: 25961237 DOI: 10.1515/hmbci.2010.078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2010] [Accepted: 12/06/2010] [Indexed: 11/15/2022]
Abstract
Sex steroids are known to regulate brain function and their role is so important that several diseases are strictly correlated with the onset of menopause when estrogen-progesterone deficiency makes neural cells much more vulnerable to toxic stimuli. Although in the past years several scientists have focused their studies on in vitro and in vivo effects of sex steroids on the brain, we are still far from complete knowledge. Indeed, contrasting results from large clinical trials have made the entire issue much more complicated. Currently we know that protective effects exerted by sex steroids depend on several factors among which the dose, the health of the cells and the type of molecule being used. In this review, we present an overview of the direct and indirect effects of estrogen and progesterone on the brain with specific focus on the molecular mechanisms by which these molecules act on neural cells.
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Possible role of resveratrol targeting estradiol and neprilysin pathways in lipopolysaccharide model of Alzheimer disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 822:107-18. [PMID: 25416980 DOI: 10.1007/978-3-319-08927-0_12] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disease that slowly destroys memory and thinking skills. It is the most common cause of dementia among older people. One of the most important hallmarks of AD is the presence of amyloid beta (Aβ) peptide in the brain that suggests that it is the primary trigger for neuronal loss. Herbal extracts have been studied over the years for their potential therapeutic effect in AD. Resveratrol (RSV), one of the most important phytoestrogens, is considered to be useful as estrogen plays an important role in AD. One of the most important amyloid degrading enzymes is neprilysin (NEP), which plays a major role in degrading Aβ, and mainly affected by estrogen. So, the aim of the present study is investigating the possible role of resveratrol in lipopolysaccharide model of AD and the implication of its possible role in regulating the estradiol and neprilysin pathways. Mice were divided into four groups: Control group (0.9 % saline), LPS group (0.8 mg/kg i.p once), Treatment group with RSV (mice were once injected with LPS then after 30 min given a dose of {4 mg/kg} RSV for 7 days), and RSV group only (mice received 4 mg/kg i.p for 7 days only). After 7 days mice were subjected to different behavioral tests using Y-maze, object recognition test, and open field tests. Estradiol and NEP level were measured using ELISA kit. Results showed RSV was able to reverse the decline in different types of memory (working, nonspatial, and locomotor functions) caused by LPS induction in mice. Moreover RSV was able to significantly increase both the estradiol level and NEP level and that may have a great role to decrease Aβ deposition as it has been confirmed that there is a link between NEP and estradiol level; by upregulation of estradiol level this consequently leads to increase in the level of NEP level, and by increasing the NEP level in brain, this lead to decrease in Aβ deposition and enhancing its degradation by NEP.
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Abstract
Estradiol effects on memory depend on hormone levels and the interaction of different estrogen receptors within neural circuits. Estradiol induces gene transcription and rapid membrane signaling mediated by estrogen receptor-alpha (ERα), estrogen receptor-beta (ERβ), and a recently characterized G-protein coupled estrogen receptor, each with distinct distributions and ability to influence estradiol-dependent signaling. Investigations using receptor specific agonists suggest that all three receptors rapidly activate kinase-signaling and have complex dose-dependent influences on memory. Research employing receptor knockout mice demonstrate that ERα maintains transcription and memory as estradiol levels decline. This work indicates a regulatory role of ERβ in transcription and cognition, which depends on estradiol levels and the function of ERα. The regulatory role of ERβ is due in part to ERβ acting as a negative regulator of ERα-mediated transcription. Vector-mediated expression of estrogen receptors in the hippocampus provides an innovative research approach and suggests that memory depends on the relative expression of ERα and ERβ interacting with estradiol levels. Notably, the ability of estradiol to improve cognition declines with advanced age along with decreased expression of estrogen receptors. Thus, it will be important for future research to determine the mechanisms that regulate estrogen receptor expression during aging.
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Affiliation(s)
- Linda A Bean
- Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Lara Ianov
- Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL, USA Genetics and Genomics Program, Genetics Institute, University of Florida, Gainesville, FL, USA
| | - Thomas C Foster
- Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL, USA Genetics and Genomics Program, Genetics Institute, University of Florida, Gainesville, FL, USA
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Clark S, Rainville J, Zhao X, Katzenellenbogen BS, Pfaff D, Vasudevan N. Estrogen receptor-mediated transcription involves the activation of multiple kinase pathways in neuroblastoma cells. J Steroid Biochem Mol Biol 2014; 139:45-53. [PMID: 24121066 DOI: 10.1016/j.jsbmb.2013.09.010] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2013] [Revised: 09/15/2013] [Accepted: 09/20/2013] [Indexed: 11/22/2022]
Abstract
While many physiological effects of estrogens (E) are due to regulation of gene transcription by liganded estrogen receptors (ERs), several effects are also mediated, at least in part, by rapid non-genomic actions of E. Though the relative importance of rapid versus genomic effects in the central nervous system is controversial, we showed previously that membrane-limited effects of E, initiated by an estradiol bovine serum albumin conjugate (E2-BSA), could potentiate transcriptional effects of 17β-estradiol from an estrogen response element (ERE)-reporter in neuroblastoma cells. Here, using specific inhibitors and activators in a pharmacological approach, we show that activation of phosphatidylinositol-3-phosphate kinase (PI3K) and mitogen activated protein kinase (MAPK) pathways, dependent on a Gαq coupled receptor signaling are important in this transcriptional potentiation. We further demonstrate, using ERα phospho-deficient mutants, that E2-BSA mediated phosphorylation of ERα is one mechanism to potentiate transcription from an ERE reporter construct. This study provides a possible mechanism by which signaling from the membrane is coupled to transcription in the nucleus, providing an integrated view of hormone signaling in the brain.
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Affiliation(s)
- Sara Clark
- Cell and Molecular Biology Department, Tulane University, New Orleans, LA 70118, United States
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da Rocha JT, Sampaio TB, Santos Neto JS, Nogueira CW, Zeni G. Cognitive effects of diphenyl diselenide and estradiol treatments in ovariectomized mice. Neurobiol Learn Mem 2012; 99:17-24. [PMID: 23085182 DOI: 10.1016/j.nlm.2012.10.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2012] [Revised: 10/08/2012] [Accepted: 10/10/2012] [Indexed: 02/09/2023]
Abstract
This study investigated the effects of co-administration of diphenyl diselenide [(PhSe)(2)] and 17β-estradiol (E(2)) on spatial reference, recognition, and working memories in ovariectomized (OVX) female mice. Sixty-day-old female adult Swiss mice were submitted to ovariectomy. From the 30th until 32nd day after ovariectomy, different doses of (PhSe)(2) (0.5-10mg/kg p.o.) were administrated to OVX mice 30min before each training of Morris Water Maze (MWM) test in order to find the highest subeffective dose for this drug. After that, OVX mice were divided into four groups: Oil, (PhSe)(2), E(2), and (PhSe)(2)+E(2). (PhSe)(2) (0.5mg/kg) and E(2) (0.1mg/kg) were administered to OVX mice from 30th to 32nd day after surgery, 30min before the training phases of behavioral tests (Open Field, MWM, Object Recognition, and T-maze). Our results demonstrated that 0.5mg/kg (PhSe)(2) plus 0.1mg/kg E(2) combined treatment improved spatial memory in the MWM test. By contrast, this same co-administration therapy was not effective in ameliorating neither delayed spontaneous alternation in the T-maze test nor object recognition memory deficits in OVX mice, although the dose of 0.5mg/kg (PhSe)(2) enhanced per se the object recognition memory in OVX mice. In conclusion, the current behavioral data suggest that a combination of (PhSe)(2) plus E(2) treatment seems to be a promising alternative to treat the cognitive decline related to menopause. Further studies should be conducted in order to determine an effective dose for (PhSe)(2) plus E(2) therapy on Object Recognition and T-maze tests.
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Affiliation(s)
- Juliana Trevisan da Rocha
- Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
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Li M, Masugi-Tokita M, Takanami K, Yamada S, Kawata M. Testosterone has sublayer-specific effects on dendritic spine maturation mediated by BDNF and PSD-95 in pyramidal neurons in the hippocampus CA1 area. Brain Res 2012; 1484:76-84. [PMID: 23010313 DOI: 10.1016/j.brainres.2012.09.028] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Revised: 09/12/2012] [Accepted: 09/16/2012] [Indexed: 11/28/2022]
Abstract
Testosterone has a number of important physiological roles and acts on peripheral target tissues and the central nervous system. Testosterone exerts many of its effects through the androgen receptor (AR). ARs are widely distributed in nervous tissues and particularly strongly expressed in hippocampal CA1 pyramidal neurons, which play critical roles in spatial memory tasks. Dendritic spines are specialized to receive synaptic inputs, and a change in spine morphology is correlated with the strength and maturity of each synapse. In this study, we used thy1-GFP transgenic male adult mice to analyze the morphology of dendritic spines in the hippocampal CA1 area. Gonadectomy (GDX) induced aberrant morphologies with less mushroom-type and more stubby- and thin-type spines in the proximal part of the stratum radiatum after two weeks. These morphological changes were also observed in the distal part of the stratum radiatum, whereas there was no change in the stratum lacunosum-moleculare after GDX. Testosterone replacement in GDX mice recovered the changes in spine types to those found in controls. To determine the mechanism of the testosterone-dependent morphological changes, we examined expression of brain-derived neurotrophic factor (BDNF) and its downstream target post-synaptic density protein 95 (PSD-95). GDX induced a significant decrease in the protein levels of BDNF and PSD-95 in the CA1 area, which were prevented by testosterone replacement. These findings reveal a novel role of testosterone in prevented the differential response properties of spine maturation in sublayers of dendritic spines in the CA1 area via the actions of BDNF and PSD-95.
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Affiliation(s)
- Meihua Li
- Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
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Belenichev IF, Odnokoz OV, Pavlov SV, Belenicheva OI, Polyakova EN. The neuroprotective activity of tamoxifen and tibolone during glutathione depletion in vitro. NEUROCHEM J+ 2012. [DOI: 10.1134/s181971241203004x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Abstract
When compared with single gene functional analysis, gene set analysis (GSA) can extract more information from gene expression profiles. Currently, several gene set methods have been proposed, but most of the methods cannot detect gene sets with a large number of minor-effect genes. Here, we propose a novel distance-based gene set analysis method. The distance between two groups of genes with different phenotypes based on gene expression should be larger if a certain gene set is significantly associated with the given phenotype. We calculated the distance between two groups with different phenotypes, estimated the significant P-values using two permutation methods and performed multiple hypothesis testing adjustments. This method was performed on one simulated data set and three real data sets. After a comparison and literature verification, we determined that the gene resampling-based permutation method is more suitable for GSA, and the centroid statistical and average linkage statistical distance methods are efficient, especially in detecting gene sets containing more minor-effect genes. We believe that this distance-based method will assist us in finding functional gene sets that are significantly related to a complex trait. Additionally, we have prepared a simple and publically available Perl and R package (http://bioinfo.hrbmu.edu.cn/dbgsa or http://cran.r-project.org/web/packages/DBGSA/).
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Frick KM. Building a better hormone therapy? How understanding the rapid effects of sex steroid hormones could lead to new therapeutics for age-related memory decline. Behav Neurosci 2012; 126:29-53. [PMID: 22289043 DOI: 10.1037/a0026660] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
A wealth of data collected in recent decades has demonstrated that ovarian sex-steroid hormones, particularly 17β-estradiol (E2), are important trophic factors that regulate the function of cognitive regions of the brain such as the hippocampus. The loss of hormone cycling at menopause is associated with cognitive decline and dementia in women, and the onset of memory decline in animal models. However, hormone therapy is not currently recommended to prevent or treat cognitive decline, in part because of its detrimental side effects. In this article, it is proposed that investigations of the rapid effects of E2 on hippocampal function be used to further the design of new drugs that mimic the beneficial effects of E2 on memory without the side effects of current therapies. A conceptual model is presented for elucidating the molecular and biochemical mechanisms through which sex-steroid hormones modulate memory, and a specific hypothesis is proposed to account for the rapid memory-enhancing effects of E2. Empirical support for this hypothesis is discussed as a means of stimulating the consideration of new directions for the development of hormone-based therapies to preserve memory function in menopausal women.
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Affiliation(s)
- Karyn M Frick
- Department of Psychology, University of Wisconsin-Milwaukee, 2441 East Hartford Avenue, Milwaukee, WI 53211, USA.
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Liu MH, Tsuang FY, Sheu SY, Sun JS, Shih CM. The protective effects of coumestrol against amyloid-β peptide- and lipopolysaccharide-induced toxicity on mice astrocytes. Neurol Res 2012; 33:663-72. [PMID: 21708076 DOI: 10.1179/1743132810y.0000000029] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
OBJECTIVES Estrogen replacement therapy can decrease the risk of developing Alzheimer's disease. Phytoestrogens have been proposed as potential alternatives to estrogen replacement therapy. The purpose of this study was to evaluate the in vitro protective effects of coumestrol on mice astrocytes. METHODS Different concentrations of coumestrol were tested for their protective efficacy against two toxic insults, lipopolysaccharide (LPS) and amyloid-beta peptide, on astrocytes. The mitochondrial activity of astrocytes was determined, and the protective efficacy and pathway were examined by their specific gene expression and protein change. RESULTS The results showed that coumestrol induced a modest but significant increase in viability of astrocytes, while the viability of astrocytes was reduced following exposure to LPS and amyloid-beta peptide. The addition of coumestrol could reverse the toxic effect induced by LPS and amyloid-beta peptide. Both the LPS and amyloid-beta peptide enhanced interleukin 1, interleukin 6, and tumor necrosis factor-alpha synthesis and these effects were inhibited by 10(-9)M coumestrol. This effect was more obvious on the LPS-induced inflammation. The estrogen receptor expression was upregulated by coumestrol, while the effect was more obvious on estrogen receptor-beta (ER-beta). These effects can be inhibited by extracellular signal-regulated kinase and c-Jun N-terminal kinase inhibitors but not p38 inhibitor. DISCUSSION The current data support a possible role for astrocytes in the mediation of neuroprotection by coumestrol. An indirect extracellular signal-regulated kinase/c-Jun N-terminal kinase signaling pathway to downregulate the expression of interleukin 1, interleukin 6, and the tumor necrosis factor-alpha cytotoxic effect may act in concert with the proposed direct ER-beta biosynethsis pathway to achieve a widespread, global protection of ER-beta positive neurons.
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Affiliation(s)
- Man-Hai Liu
- School of Pharmacy, Taipei Medical University, Taiwan
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Abstract
Sex steroids exert actions of paramount importance on brain cells. They contribute to shape the central nervous system during embryo development. They modulate the formation and the turnover of the interconnections between neurons. They control the function of glial cells. And they do it through a signaling machinery that is apparently simple, but that hides a level of complexity that has been unveiled only in part. Different receptor isoforms, different interactions between receptors and co-regulators, chains of events originating at the cell membrane and leading to effects in the nucleus (or the other way around) all interact to determine selective modulations of brain cells. All these actions end up in phenomenal effects on brain function that change through adolescence, pregnancy, adulthood, up to menopause and ageing. Many of these actions are relevant for degenerative processes and research may offer soon new strategies to counteract these diseases.
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Affiliation(s)
- Paolo Mannella
- Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy
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Estrogen receptor-alpha 36 mediates mitogenic antiestrogen signaling in ER-negative breast cancer cells. PLoS One 2012; 7:e30174. [PMID: 22276155 PMCID: PMC3261853 DOI: 10.1371/journal.pone.0030174] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2011] [Accepted: 12/14/2011] [Indexed: 11/23/2022] Open
Abstract
It is prevailingly thought that the antiestrogens tamoxifen and ICI 182, 780 are competitive antagonists of the estrogen-binding site of the estrogen receptor-alpha (ER-α). However, a plethora of evidence demonstrated both antiestrogens exhibit agonist activities in different systems such as activation of the membrane-initiated signaling pathways. The mechanisms by which antiestrogens mediate estrogen-like activities have not been fully established. Previously, a variant of ER-α, EP–α36, has been cloned and showed to mediate membrane-initiated estrogen and antiestrogen signaling in cells only expressing ER-α36. Here, we investigated the molecular mechanisms underlying the antiestrogen signaling in ER-negative breast cancer MDA-MB-231 and MDA-MB-436 cells that express high levels of endogenous ER-α36. We found that the effects of both 4-hydoxytamoxifen (4-OHT) and ICI 182, 780 (ICI) exhibited a non-monotonic, or biphasic dose response curve; antiestrogens at low concentrations, elicited a mitogenic signaling pathway to stimulate cell proliferation while at high concentrations, antiestrogens inhibited cell growth. Antiestrogens at l nM induced the phosphorylation of the Src-Y416 residue, an event to activate Src, while at 5 µM induced Src-Y527 phosphorylation that inactivates Src. Antiestrogens at 1 nM also induced phosphorylation of the MAPK/ERK and activated the Cyclin D1 promoter activity through the Src/EGFR/STAT5 pathways but not at 5 µM. Knock-down of ER-α36 abrogated the biphasic antiestrogen signaling in these cells. Our results thus indicated that ER-α36 mediates biphasic antiestrogen signaling in the ER-negative breast cancer cells and Src functions as a switch of antiestrogen signaling dependent on concentrations of antiestrogens through the EGFR/STAT5 pathway.
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Yao J, Brinton RD. Estrogen regulation of mitochondrial bioenergetics: implications for prevention of Alzheimer's disease. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2012; 64:327-71. [PMID: 22840752 PMCID: PMC3970844 DOI: 10.1016/b978-0-12-394816-8.00010-6] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. Increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. Compromised aerobic glycolysis pathway coupled with oxidative stress is first accompanied by a shift toward a ketogenic pathway that eventually progresses into fatty acid oxidation (FAO) pathways and leads to white matter degeneration and overproduction and mitochondrial accumulation of β-amyloid. Estrogen-induced signaling pathways converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis coupled with citric acid cycle-driven oxidative phosphorylation to potentiate ATP (Adenosine triphosphate) generation. In addition to potentiated mitochondrial bioenergetics, estrogen also enhances neural survival and health through maintenance of calcium homeostasis, promotion of antioxidant defense against free radicals, efficient cholesterol trafficking, and beta amyloid clearance. Significantly, the convergence of E2 mechanisms of action onto mitochondria is also a potential point of vulnerability when activated in diseased neurons that exacerbates degeneration through increased load on dysregulated calcium homeostasis. The "healthy cell bias of estrogen action" hypothesis examines the role that regulating mitochondrial function and bioenergetics play in promoting neural health and the mechanistic crossroads that lead to divergent outcomes following estrogen exposure. As the continuum of neurological health progresses from healthy to unhealthy, so too do the benefits of estrogen or hormone therapy.
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Affiliation(s)
- Jia Yao
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
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Espinosa-Raya J, Neri-Gómez T, Orozco-Suárez S, Campos MG, Guerra-Araiza C. Chronic administration of tibolone modulates anxiety-like behavior and enhances cognitive performance in ovariectomized rats. Horm Behav 2012; 61:76-83. [PMID: 22067260 DOI: 10.1016/j.yhbeh.2011.10.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2011] [Revised: 10/17/2011] [Accepted: 10/25/2011] [Indexed: 11/28/2022]
Abstract
Hormone replacement therapy (HRT) may be prescribed to prevent the symptoms of menopause. This therapy may include estrogenic and/or progestin components and may increase the incidence of endometrial and breast cancers. Tibolone (TIB), which is also made up of estrogen and progestin components, is often used to reduce the impact of HRT. However, the effect of TIB on the processes of learning, memory and anxiety has yet to be fully elucidated. The aim of this study was to evaluate the long-term effect on learning, memory processes and anxiety in ovariectomized rats caused by different doses of TIB (0 mg/kg, 0.01 mg/kg, 0.1 mg/kg 1.0 mg/kg and 10 mg/kg, administered daily via the oral route for 18 weeks). Two behavioral animal models, the autoshaping and T maze models were employed. The concentrations of acetyl choline transferase (ChAT) and tryptophan hydroxylase (TPH) in the hippocampus were directly measured by Western blot. No significant changes were observed in the autoshaping model and spontaneous activity test. In the T maze, increased latency was observed with TIB doses of 1 and 10 mg/kg compared to the vehicle. We observed that the ChAT content decreased with increasing doses of TIB, whereas TPH content increased with doses of 1 and 10 mg/kg of TIB. These data indicate that high doses of TIB improved emotional learning, which may be related to the modulation of the cholinergic and serotonergic systems by TIB.
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Affiliation(s)
- Judith Espinosa-Raya
- Escuela Superior de Medicina del Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón S/N, Col. Sto. Tomás, México D.F. 11340, Mexico
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Numakawa T, Matsumoto T, Numakawa Y, Richards M, Yamawaki S, Kunugi H. Protective Action of Neurotrophic Factors and Estrogen against Oxidative Stress-Mediated Neurodegeneration. J Toxicol 2011; 2011:405194. [PMID: 21776259 PMCID: PMC3135156 DOI: 10.1155/2011/405194] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2011] [Revised: 02/28/2011] [Accepted: 03/29/2011] [Indexed: 01/01/2023] Open
Abstract
Oxidative stress is involved in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Low levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important for maintenance of neuronal function, though elevated levels lead to neuronal cell death. A complex series of events including excitotoxicity, Ca(2+) overload, and mitochondrial dysfunction contributes to oxidative stress-mediated neurodegeneration. As expected, many antioxidants like phytochemicals and vitamins are known to reduce oxidative toxicity. Additionally, growing evidence indicates that neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and estrogens significantly prevent neuronal damage caused by oxidative stress. Here, we review and discuss recent studies addressing the protective mechanisms of neurotrophic factors and estrogen within this system.
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Affiliation(s)
- Tadahiro Numakawa
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan
- Core Research for Evolutional Science and Technology Program (CREST), Japan Science and Technology Agency (JST), Saitama 332-0012, Japan
| | - Tomoya Matsumoto
- Core Research for Evolutional Science and Technology Program (CREST), Japan Science and Technology Agency (JST), Saitama 332-0012, Japan
- Department of Psychiatry and Neurosciences, Division of Frontier Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| | - Yumiko Numakawa
- Peptide-prima Co., Ltd., 1-25-81, Nuyamazu, Kumamoto 861-2102, Japan
| | - Misty Richards
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan
- The Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA
| | - Shigeto Yamawaki
- Core Research for Evolutional Science and Technology Program (CREST), Japan Science and Technology Agency (JST), Saitama 332-0012, Japan
- Department of Psychiatry and Neurosciences, Division of Frontier Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| | - Hiroshi Kunugi
- Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan
- Core Research for Evolutional Science and Technology Program (CREST), Japan Science and Technology Agency (JST), Saitama 332-0012, Japan
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Abstract
Women are more susceptible to a variety of autoimmune diseases including systemic lupus erythematosus (SLE), multiple sclerosis (MS), primary biliary cirrhosis, rheumatoid arthritis and Hashimoto's thyroiditis. This increased susceptibility in females compared to males is also present in animal models of autoimmune diseases such as spontaneous SLE in (NZBxNZW)F1 and NZM.2328 mice, experimental autoimmune encephalomyelitis (EAE) in SJL mice, thyroiditis, Sjogren's syndrome in MRL/Mp-lpr/lpr mice and diabetes in non-obese diabetic mice. Indeed, being female confers a greater risk of developing these diseases than any single genetic or environmental risk factor discovered to date. Understanding how the state of being female so profoundly affects autoimmune disease susceptibility would accomplish two major goals. First, it would lead to an insight into the major pathways of disease pathogenesis and, secondly, it would likely lead to novel treatments which would disrupt such pathways.
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Affiliation(s)
- Rhonda Voskuhl
- Professor, UCLA Dept, of Neurology, Jack H Skirball Chair for Multiple Sclerosis Research, Director, UCLA Multiple Sclerosis Program, Neuroscience Research Building 1, Room 475D, 635 Charles Young Drive South, Los Angeles, CA 90095, USA.
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40
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Pluchino N, Bucci F, Cela V, Cubeddu A, Genazzani AR. Menopause and Mental Well-Being: Timing of Symptoms and Timing of Hormone Treatment. WOMENS HEALTH 2011; 7:71-80. [DOI: 10.2217/whe.10.80] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
In the aftermath of the Women's Health Initiative studies, both the clinical and basic science communities had to sort out divergent results among experimental findings, observational data and randomized controlled trials in order to establish a shared analysis. The scientific community formally debates the role of different HRT formulations, hormone doses, time of treatment initiation since the menopause and the age of treated women. Basic scientists demonstrated that the multiple neuroprotective effects of estrogen on brain cells may induce a differential biological response according to the time of treatment. Progesterone (but not all synthetic progestins) also has pivotal neuroactive functions in animal models of reproductive aging. Additionally, epidemiological surveys provide information regarding the detrimental role of hypogonadism on mental well-being. The present article briefly summarizes current evidence supporting the neuroactive role of estrogen, with reference to the clinical finding sustaining the intriguing hypothesis of the early female brain senescence as a highly responsive period to estrogen treatment.
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Affiliation(s)
- Nicola Pluchino
- Department of Reproductive Medicine & Child Development, Division of Gynecology & Obstetrics, University of Pisa, Pisa, Italy
| | - Fiorella Bucci
- Department of Reproductive Medicine & Child Development, Division of Gynecology & Obstetrics, University of Pisa, Pisa, Italy
| | - Vito Cela
- Department of Reproductive Medicine & Child Development, Division of Gynecology & Obstetrics, University of Pisa, Pisa, Italy
| | - Alessandra Cubeddu
- Department of Reproductive Medicine & Child Development, Division of Gynecology & Obstetrics, University of Pisa, Pisa, Italy
| | - Andrea Riccardo Genazzani
- Department of Reproductive Medicine & Child Development, Division of Gynecology & Obstetrics, University of Pisa, Pisa, Italy
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Numakawa T, Yokomaku D, Richards M, Hori H, Adachi N, Kunugi H. Functional interactions between steroid hormones and neurotrophin BDNF. World J Biol Chem 2010; 1:133-43. [PMID: 21540998 PMCID: PMC3083963 DOI: 10.4331/wjbc.v1.i5.133] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2010] [Revised: 05/20/2010] [Accepted: 05/24/2010] [Indexed: 02/05/2023] Open
Abstract
Brain-derived neurotrophic factor (BDNF), a critical neurotrophin, regulates many neuronal aspects including cell differentiation, cell survival, neurotransmission, and synaptic plasticity in the central nervous system (CNS). Though BDNF has two types of receptors, high affinity tropomyosin-related kinase (Trk)B and low affinity p75 receptors, BDNF positively exerts its biological effects on neurons via activation of TrkB and of resultant intracellular signaling cascades including mitogen-activated protein kinase/extracellular signal-regulated protein kinase, phospholipase Cγ, and phosphoinositide 3-kinase pathways. Notably, it is possible that alteration in the expression and/or function of BDNF in the CNS is involved in the pathophysiology of various brain diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, and mental disorders. On the other hand, glucocorticoids, stress-induced steroid hormones, also putatively contribute to the pathophysiology of depression. Interestingly, in addition to the reduction in BDNF levels due to increased glucocorticoid exposure, current reports demonstrate possible interactions between glucocorticoids and BDNF-mediated neuronal functions. Other steroid hormones, such as estrogen, are involved in not only sexual differentiation in the brain, but also numerous neuronal events including cell survival and synaptic plasticity. Furthermore, it is well known that estrogen plays a role in the pathophysiology of Parkinson’s disease, Alzheimer’s disease, and mental illness, while serving to regulate BDNF expression and/or function. Here, we present a broad overview of the current knowledge concerning the association between BDNF expression/function and steroid hormones (glucocorticoids and estrogen).
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Affiliation(s)
- Tadahiro Numakawa
- Tadahiro Numakawa, Misty Richards, Hiroaki Hori, Naoki Adachi, Hiroshi Kunugi, Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8502, Japan
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Frick KM, Fernandez SM, Harburger LL. A new approach to understanding the molecular mechanisms through which estrogens affect cognition. Biochim Biophys Acta Gen Subj 2009; 1800:1045-55. [PMID: 19913600 DOI: 10.1016/j.bbagen.2009.11.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2009] [Revised: 10/23/2009] [Accepted: 11/02/2009] [Indexed: 12/23/2022]
Abstract
Traditional approaches to the study of hormones and cognition have been primarily observational or correlational in nature. Because this work does not permit causal relationships to be identified, very little is known about the specific molecules and cellular events through which hormones affect cognitive function. In this review, we propose a new approach to study hormones and memory, where the systematic blocking of cellular events can reveal which such events are necessary for hormones to influence memory consolidation. The discussion will focus on the modulation of the hippocampus and hippocampal memory by estrogens, given the extensive literature on this subject, and will illustrate how the application of this approach is beginning to reveal important new information about the molecular mechanisms through which estrogens modulate memory consolidation. The clinical relevance of this work will also be discussed.
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Affiliation(s)
- Karyn M Frick
- Department of Psychology, Yale University, New Haven, CT 06520, USA.
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43
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Brinton RD. Estrogen-induced plasticity from cells to circuits: predictions for cognitive function. Trends Pharmacol Sci 2009; 30:212-22. [PMID: 19299024 PMCID: PMC3167490 DOI: 10.1016/j.tips.2008.12.006] [Citation(s) in RCA: 220] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2008] [Revised: 12/03/2008] [Accepted: 12/05/2008] [Indexed: 01/29/2023]
Abstract
Controversy regarding estrogen action in the brain remains at the forefront of basic, translational and clinical science for women's health. Here, I provide an integrative analysis of estrogen-inducible plasticity and posit it as a strategy for predicting cognitive domains affected by estrogen in addition to sources of variability. Estrogen enhancement of plasticity is evidenced by increases in neurogenesis, neural network connectivity and synaptic transmission. In parallel, estrogen increases glucose transport, aerobic glycolysis and mitochondrial function to provide the ATP necessary to sustain increased energetic demand. The pattern of plasticity predicts that estrogen would preferentially affect cognitive tasks of greater complexity, temporal demand and associative challenge. Thus, estrogen deprivation should be associated with decrements in these functions. Estrogen regulation of plasticity and bioenergetics provides a framework for predicting estrogen-dependent cognitive functions while also identifying sources of variability and potential biomarkers for identifying women appropriate for hormone therapy.
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Affiliation(s)
- Roberta Diaz Brinton
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy Pharmaceutical Sciences Center, Los Angeles, CA 90033, USA.
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44
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Occhiuto F, Palumbo DR, Samperi S, Zangla G, Pino A, De Pasquale R, Circosta C. The isoflavones mixture from Trifolium pratense L. protects HCN 1-A neurons from oxidative stress. Phytother Res 2009; 23:192-6. [PMID: 18693301 DOI: 10.1002/ptr.2584] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Oxidative stress-induced neuronal cell death has been implicated in different neurological disorders and neurodegenerative diseases such as Alzheimer's disease and Parkinson's. Using the Alzheimer's disease-associated hydrogen peroxide (H(2)O(2)), we investigated the neuroprotective efficacy of a natural mixture of phytoestrogenic isoflavones (genistein, daidzein, biochanin A and formononetin) from Trifolium pratense L. (Red clover) against oxidative stress-induced cell death in human cortical cell line HCN 1-A maintained in culture. Neuronal viability was determined by MTT or trypan blue test and neuronal integrity by morphological analysis.The results obtained indicate that exposure of HCN 1-A cell cultures to hydrogen peroxide resulted in a concentration-dependent decrease in neuron viability. Concentration of H(2)O(2) ranging from 50 to 200 microg/ml were toxic to these cultures. A 24-hour pretreatment with 0.5, 1 and 2 microg/ml isoflavones extract significantly increased cell survival as evidenced by MTT or trypan blue test and significantly prevented the morphological disruption caused by H(2)O(2) as shown by microscopical inspection, indicating that neurons treated with isoflavones were protected from the cell death induced by H(2)O(2) exposure. These findings imply that the neuroprotective effect of isoflavones extract is partly associated with its antioxidant activity. Further, results of these investigations indicate that although isoflavones extract exert a neuroprotective effect, it do not promoted cortical neuron process outgrowth.
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Affiliation(s)
- Francesco Occhiuto
- Pharmaco-Biological Department, School of Pharmacy, University of Messina, Messina Italy.
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Frick KM. Estrogens and age-related memory decline in rodents: what have we learned and where do we go from here? Horm Behav 2009; 55:2-23. [PMID: 18835561 PMCID: PMC2664384 DOI: 10.1016/j.yhbeh.2008.08.015] [Citation(s) in RCA: 165] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2008] [Revised: 08/28/2008] [Accepted: 08/29/2008] [Indexed: 01/20/2023]
Abstract
The question of whether ovarian hormone therapy can prevent or reduce age-related memory decline in menopausal women has been the subject of much recent debate. Although numerous studies have demonstrated a beneficial effect of estrogen and/or progestin therapy for certain types of memory in menopausal women, recent clinical trials suggest that such therapy actually increases the risk of cognitive decline and dementia. Because rodent models have been frequently used to examine the effects of age and/or ovarian hormone deficiency on mnemonic function, rodent models of age-related hormone and memory decline may be useful in helping to resolve this issue. This review will focus on evidence suggesting that estradiol modulates memory, particularly hippocampal-dependent memory, in young and aging female rats and mice. Various factors affecting the mnemonic response to estradiol in aging females will be highlighted to illustrate the complications inherent to studies of estrogen therapy in aging females. Avenues for future development of estradiol-based therapies will also be discussed, and it is argued that an approach to drug development based on identifying the molecular mechanisms underlying estrogenic modulation of memory may lead to promising future treatments for reducing age-related mnemonic decline.
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Affiliation(s)
- Karyn M Frick
- Department of Psychology, Yale University, New Haven, CT 06520, USA.
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Wang JM, Brinton RD. Allopregnanolone-induced rise in intracellular calcium in embryonic hippocampal neurons parallels their proliferative potential. BMC Neurosci 2008; 9 Suppl 2:S11. [PMID: 19090984 PMCID: PMC2604895 DOI: 10.1186/1471-2202-9-s2-s11] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Background Factors that regulate intracellular calcium concentration are known to play a critical role in brain function and neural development, including neural plasticity and neurogenesis. We previously demonstrated that the neurosteroid allopregnanolone (APα; 5α-pregnan-3α-ol-20-one) promotes neural progenitor proliferation in vitro in cultures of rodent hippocampal and human cortical neural progenitors, and in vivo in triple transgenic Alzheimer's disease mice dentate gyrus. We also found that APα-induced proliferation of neural progenitors is abolished by a calcium channel blocker, nifedipine, indicating a calcium dependent mechanism for the proliferation. Methods In the present study, we investigated the effect of APα on the regulation of intracellular calcium concentration in E18 rat hippocampal neurons using ratiometric Fura2-AM imaging. Results Results indicate that APα rapidly increased intracellular calcium concentration in a dose-dependent and developmentally regulated manner, with an EC50 of 110 ± 15 nM and a maximal response occurring at three days in vitro. The stereoisomers 3β-hydroxy-5α-hydroxy-pregnan-20-one, and 3β-hydroxy-5β-hydroxy-pregnan-20-one, as well as progesterone, were without significant effect. APα-induced intracellular calcium concentration increase was not observed in calcium depleted medium and was blocked in the presence of the broad spectrum calcium channel blocker La3+, or the L-type calcium channel blocker nifedipine. Furthermore, the GABAA receptor blockers bicuculline and picrotoxin abolished APα-induced intracellular calcium concentration rise. Conclusion Collectively, these data indicate that APα promotes a rapid, dose-dependent, stereo-specific, and developmentally regulated increase of intracellular calcium concentration in rat embryonic hippocampal neurons via a mechanism that requires both the GABAA receptor and L-type calcium channel. These data suggest that APα-induced intracellular calcium concentration increase serves as the initiation mechanism whereby APα promotes neurogenesis.
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Affiliation(s)
- Jun Ming Wang
- Department of Pharmacology and Pharmaceutical Sciences and Program in Neuroscience, University of Southern California, Los Angeles, CA 90089, USA.
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Brinton RD. The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications. Trends Neurosci 2008; 31:529-37. [PMID: 18774188 PMCID: PMC10124615 DOI: 10.1016/j.tins.2008.07.003] [Citation(s) in RCA: 283] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2008] [Revised: 07/16/2008] [Accepted: 07/17/2008] [Indexed: 01/18/2023]
Abstract
The 'healthy cell bias of estrogen action' hypothesis examines the role that regulating mitochondrial function and bioenergetics play in promoting neural health and the mechanistic crossroads that lead to divergent outcomes following estrogen exposure. Estrogen-induced signaling pathways in hippocampal and cortical neurons converge upon the mitochondria to enhance aerobic glycolysis coupled to the citric acid cycle, mitochondrial respiration and ATP generation. Convergence of estrogen-induced signaling onto mitochondria is also a point of vulnerability when activated in diseased neurons which exacerbates degeneration through increased load on dysregulated calcium homeostasis. As the continuum of neurological health progresses from healthy to unhealthy so too do the benefits of estrogen or hormone therapy. The healthy cell bias of estrogen action hypothesis provides a lens through which to assess disparities in outcomes across basic and clinical science and on which to predict outcomes of estrogen interventions for sustaining neurological health and preventing age-associated neurodegenerative diseases such as Alzheimer's.
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Affiliation(s)
- Roberta Diaz Brinton
- Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy Pharmaceutical Sciences Center, Los Angeles, CA 90033, USA.
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Xu XW, Shi C, He ZQ, Ma CM, Chen WH, Shen YP, Guo Q, Shen CJ, Xu J. Effects of phytoestrogen on mitochondrial structure and function of hippocampal CA1 region of ovariectomized rats. Cell Mol Neurobiol 2008; 28:875-86. [PMID: 18311520 PMCID: PMC11515463 DOI: 10.1007/s10571-008-9265-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2007] [Accepted: 02/02/2008] [Indexed: 10/22/2022]
Abstract
The present study was undertaken to evaluate whether estrogen deprivation might lead to mitochondrial alteration of hippocampal neurons of ovariectomized (OVX) rats, and to evaluate the protective effect of estrogen and phytoestrogen on the mitochondrial alteration. First, OVX rats were used to mimic the pathologic changes of neurodegeneration of postmenopausal female, and we looked into the alteration of the mitochondrial ultrastructure and ATP content of hippocampal CA1 region after ovariectomy on different phase by transmission electron microscope (TEM) and reversed-phase high-performance liquid chromatography (HPLC), and found the best phase points of the alteration of the mitochondrial ultrastructure and ATP content. Next, estrogen and phytoestrogen were administered to the OVX rats for the protective effects on the mitochondrial ultrastructure and ATP content. Meanwhile, the density, size, shape, and distribution parameters of mitochondrial ultrastructure were analyzed according to the morphometry principle. The experimental results presented that (1) The alteration of mitochondrial ultrastructure elicited by ovariectomy worsened with the days going on, and the changes were the most noteworthy in volume density (Vv), average surface area (S), specific surface area (delta), and particle dispersity (Clambdaz) on 12th day (P < 0.05 or P < 0.01). Moreover, there was no statistical significance of the numerical density (Nv) among the five groups in the first step experiment. (2) The treatment with estrogen, genistein (Gs), and ipriflavone (Ip) significantly reversed the effect elicited by ovariectomy on Vv, S, delta, Clambdaz, Nv, and particle average diameter (D) of mitochondria of hippocampal CA1 region (P < 0.05). (3) Furthermore, ATP content of hippocampal CA1 region after ovariectomy declined significantly on 7th day (P < 0.05), and estrogen and phytoestrogen could reverse the alteration (P < 0.05). Taken together, these results revealed that phytoestrogen may have a protective role against the neurodegeneration after menopause via protecting mitochondrial structure and functions. Phytoestrogen may be a good alternative as a novel therapeutic strategy for menopausal syndrome.
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Affiliation(s)
- Xiao-Wu Xu
- Department of Anatomy, Zhongshan School of Medicine, Sun Yat-Sen University, NO.74, ZhongShan 2 Road, Guangzhou, 510080 China
- Department of Anatomy, College of Preclinical Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006 China
| | - Chun Shi
- Department of Anatomy, Zhongshan School of Medicine, Sun Yat-Sen University Guangzhou, Guangdong, 510080 China
| | - Zhen-Quan He
- Department of Anatomy, College of Preclinical Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006 China
| | - Chun-Mei Ma
- Department of Anatomy, College of Preclinical Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006 China
| | - Wen-Hua Chen
- Department of Anatomy, College of Preclinical Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006 China
| | - Yi-Ping Shen
- Department of Anatomy, College of Preclinical Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006 China
| | - Qiang Guo
- Department of Anatomy, College of Preclinical Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006 China
| | - Chuan-Jun Shen
- Department of Anatomy, College of Preclinical Medicine, Guangzhou University of Traditional Chinese Medicine, Guangzhou, 510006 China
| | - Jie Xu
- Department of Anatomy, Zhongshan School of Medicine, Sun Yat-Sen University, NO.74, ZhongShan 2 Road, Guangzhou, 510080 China
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Simpkins JW, Yang SH, Sarkar SN, Pearce V. Estrogen actions on mitochondria--physiological and pathological implications. Mol Cell Endocrinol 2008; 290:51-9. [PMID: 18571833 PMCID: PMC2737506 DOI: 10.1016/j.mce.2008.04.013] [Citation(s) in RCA: 117] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2008] [Revised: 04/08/2008] [Accepted: 04/10/2008] [Indexed: 02/07/2023]
Abstract
Estrogens are potent neuroprotective hormones and mitochondria are the site of cellular life-death decisions. As such, it is not surprising that we and others have shown that estrogens have remarkable effects on mitochondrial function. Herein we provide evidence for a primary effect of estrogens on mitochondrial function, achieved in part by the import of estrogen receptor beta (ERbeta) into the mitochondria where it mediates a number of estrogen actions on this vital organelle. ERbeta is imported into the mitochondria, through tethering to cytosolic chaperone protein and/or through direct interaction with mitochondrial import proteins. In the mitochondria, ERbeta can affect transcription of critical mitochondrial genes through the interaction with estrogen response elements (ERE) or through protein-protein interactions with mitochondrially imported transcription factors. The potent effects of estrogens on mitochondrial function, particularly during mitochondrial stress, argues for a role of estrogens in the treatment of mitochondrial defects in chronic neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) and more acute conditions of mitochondrial compromise, like cerebral ischemia and traumatic brain injury.
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Affiliation(s)
- James W Simpkins
- Department of Pharmacology & Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA.
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Luoma JI, Boulware MI, Mermelstein PG. Caveolin proteins and estrogen signaling in the brain. Mol Cell Endocrinol 2008; 290:8-13. [PMID: 18502030 PMCID: PMC2565274 DOI: 10.1016/j.mce.2008.04.005] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2008] [Accepted: 04/05/2008] [Indexed: 01/08/2023]
Abstract
Best described outside the nervous system, caveolins are structural proteins that form caveolae, functional microdomains at the plasma membrane that cluster related signaling molecules. Caveolin-associated proteins include G protein-coupled receptors and G proteins, receptor tyrosine kinases, as well as protein kinases, ion channels and various other signaling enzymes. Not surprisingly, a wide array of biological disorders are thought to be rooted in caveolin dysfunction. In addition, caveolins traffic and cluster estrogen receptors to caveolae. Interactions between the estrogen receptors ERalpha and ERbeta with caveolins appear critical in many non-neuronal cell types, e.g., disruption of normal function may underlie many forms of breast cancer. Recent findings suggest caveolins may also play an essential role in membrane estrogen receptor function in the nervous system. Not only are they expressed in neurons and glia, but different caveolin isoforms also appear necessary to generate distinct functional signaling complexes. With membrane estrogen receptors responsible for the efficient activation of a multitude of intracellular signaling pathways, which in turn influence a wide variety of nervous system functions, caveolin proteins are poised to act as the central coordinators of these processes.
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Affiliation(s)
- Jessie I Luoma
- Department of Neuroscience, University of Minnesota, 6-145 Jackson Hall, 321 Church Street S.E., Minneapolis, MN 55455, USA
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