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Islas-Preciado D, Estrada-Camarena E, Galea LAM. Menstrually-related mood disorders and postpartum depression: Convergent aspects in aetiology. Front Neuroendocrinol 2025; 76:101171. [PMID: 39638001 DOI: 10.1016/j.yfrne.2024.101171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 11/13/2024] [Accepted: 12/02/2024] [Indexed: 12/07/2024]
Abstract
Females diagnosed with Menstrually-related mood disorders (MRMDs) have more risk to develop postpartum depression (PPD). There are overlapping symptoms between MRMDs and PPD such as anxiety, depressed mood, irritability, that can contribute to a lower quality of life. MRMDs and PPD share components in their etiology such as dramatic hormonal oscillations, and alterations in Hypothalamus-Pituitary-Adrenal (HPA) axis activity that may impair GABAergic neurotransmission. As well, stressful events that impact HPA regulation may play an important role in the etiology of MRMDs and PPD. Here we review common hormone fluctuations across the menstrual cycle and pregnancy/postpartum to identify shared pathways that could contribute to greater sensitivity in people with MRMDs and PPD. This review summarizes hormone sensitivity, HPA axis activity and neurosteroids effects on GABAergic transmission and the potential role of chronic stress in developing MRMDs and PPD. In addition, other potential etiopathological factors, such as serotonin and the immune system, are discussed. Investigating the etiopathology of MRMDs and PDD will help to better understand the complexity of factors involved in these disorders that affect females across the reproductive years.
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Affiliation(s)
- D Islas-Preciado
- Laboratorio de Neuropsicofarmacología, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría "Ramón de la Fuente Muñíz", Ciudad de México, México; Centre for Brain Health, University of British Columbia, Vancouver, Canada; Laboratorio de Neuromodulación, Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría "Ramón de la Fuente Muñíz", Ciudad de México, México.
| | - E Estrada-Camarena
- Laboratorio de Neuropsicofarmacología, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría "Ramón de la Fuente Muñíz", Ciudad de México, México
| | - L A M Galea
- Centre for Brain Health, University of British Columbia, Vancouver, Canada; Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, ON, Canada.
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Hirst JJ, Palliser HK, Pavy C, Shaw JC, Moloney RA. Neurosteroid replacement approaches for improving outcomes after compromised pregnancies and preterm birth. Front Neuroendocrinol 2025; 76:101169. [PMID: 39622477 DOI: 10.1016/j.yfrne.2024.101169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 11/08/2024] [Accepted: 11/28/2024] [Indexed: 12/12/2024]
Abstract
The levels of the key neurosteroid of pregnancy, allopregnanolone, are very high in the fetal and maternal brain compared to after birth. These levels are maintained by the placenta which forms a placental connection to fetal brain development. Maternal stresses depress placental synthesis resulting in a fall in allopregnanolone levels leading to deficits in myelination that continue into childhood. This contributes to an increased incidence of behavioural disorders. Supplementing neurosteroid action with allopregnanolone analogues or raising endogenous production with mitochondrial translocator protein (TSPO) ligands reverses these deficits. Preterm birth leads to an early dramatic loss of neurosteroid support for brain development leading to marked deficits in myelination and susceptibility to hypoxic-ischaemic injury. Postnatal treatment with the allopregnanolone analogue ganaxolone improves myelination and reduces hyperactive behaviour. TSPO ligands such as emapunil have been shown to improve oligodendrocyte maturation. These findings support the use of allopregnanolone supplementation approaches after pregnancy compromises to improve outcome.
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Affiliation(s)
- Jonathan J Hirst
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
| | - Hannah K Palliser
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia; Hunter Medical Research Institute, Mothers and Babies Research Program, Newcastle, Australia
| | - Carlton Pavy
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia; Hunter Medical Research Institute, Mothers and Babies Research Program, Newcastle, Australia
| | - Julia C Shaw
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia; Hunter Medical Research Institute, Mothers and Babies Research Program, Newcastle, Australia
| | - Roisin A Moloney
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia; Hunter Medical Research Institute, Mothers and Babies Research Program, Newcastle, Australia
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Chen X, Zhou YN, Lu XZ, Li RJ, Xiong YF, Sheng X, Zhu WW. Cognitive dysfunction in schizophrenia patients caused by down-regulation of γ-aminobutyric acid receptor subunits. World J Psychiatry 2024; 14:784-793. [PMID: 38984326 PMCID: PMC11230097 DOI: 10.5498/wjp.v14.i6.784] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/25/2024] [Accepted: 05/10/2024] [Indexed: 06/19/2024] Open
Abstract
BACKGROUND The expression pattern of gamma aminobutyric acid (GABA) receptor subunits are commonly altered in patients with schizophrenia, which may lead to nerve excitation/inhibition problems, affecting cognition, emotion, and behavior. AIM To explore GABA receptor expression and its relationship with schizophrenia and to provide insights into more effective treatments. METHODS This case-control study enrolled 126 patients with schizophrenia treated at our hospital and 126 healthy volunteers who underwent physical examinations at our hospital during the same period. The expression levels of the GABA receptor subunits were detected using 1H-magnetic resonance spectroscopy. The recognized cognitive battery tool, the MATRICS Consensus Cognitive Battery, was used to evaluate the scores for various dimensions of cognitive function. The correlation between GABA receptor subunit downregulation and schizophrenia was also analyzed. RESULTS Significant differences in GABA receptor subunit levels were found between the case and control groups (P < 0.05). A significant difference was also found between the case and control groups in terms of cognitive function measures, including attention/alertness and learning ability (P < 0.05). Specifically, as the expression levels of GABRA1 (α1 subunit gene), GABRB2 (β2 subunit gene), GABRD (δ subunit), and GABRE (ε subunit) decreased, the severity of the patients' condition increased gradually, indicating a positive correlation between the downregulation of these 4 receptor subunits and schizophrenia (P < 0.05). However, the expression levels of GABRA5 (α5 subunit gene) and GABRA6 (α6 subunit gene) showed no significant correlation with schizophrenia (P > 0.05). CONCLUSION Downregulation of the GABA receptor subunits is positively correlated with schizophrenia. In other words, when GABA receptor subunits are downregulated in patients, cognitive impairment becomes more severe.
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Affiliation(s)
- Xi Chen
- Department of Child and Adolescent Psychiatric, Brain Hospital of Hunan Province, The Second People’s Hospital of Hunan Province, Changsha 410007, Hunan Province, China
| | - Ya-Nan Zhou
- Department of Child and Adolescent Psychiatric, Brain Hospital of Hunan Province, The Second People’s Hospital of Hunan Province, Changsha 410007, Hunan Province, China
| | - Xiao-Zi Lu
- Department of Psychiatry, Qingdao Mental Health Center, Qingdao 266034, Shandong Province, China
| | - Ren-Jiao Li
- Department of Child and Adolescent Psychiatric, Brain Hospital of Hunan Province, The Second People’s Hospital of Hunan Province, Changsha 410007, Hunan Province, China
| | - Yi-Fan Xiong
- Department of Psychiatry, Brain Hospital of Hunan Province, The Second People’s Hospital of Hunan Province, Changsha 410007, Hunan Province, China
| | - Xia Sheng
- Department of Child and Adolescent Psychiatric, Brain Hospital of Hunan Province, The Second People’s Hospital of Hunan Province, Changsha 410007, Hunan Province, China
| | - Wei-Wei Zhu
- Department of Sleep Disorders and Neurosis, Brain Hospital of Hunan Province, The Second People’s Hospital of Hunan Province, Changsha 410007, Hunan Province, China
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Evans-Strong A, Walton N, Blandino K, Roper ATC, Donaldson ST, Lewis M, Maguire J. Witnessed trauma exposure induces fear in mice through a reduction in endogenous neurosteroid synthesis. J Neuroendocrinol 2024; 36:e13378. [PMID: 38482748 PMCID: PMC11091913 DOI: 10.1111/jne.13378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 02/17/2024] [Accepted: 02/19/2024] [Indexed: 03/27/2024]
Abstract
Neurosteroids have been implicated in the pathophysiology of post-traumatic stress disorder (PTSD). Allopregnanolone is reduced in subsets of individuals with PTSD and has been explored as a novel treatment strategy. Both direct trauma exposure and witnessed trauma are risk factors for PTSD; however, the role of neurosteroids in the behavioral outcomes of these unique experiences has not been explored. Here, we investigate whether observational fear is associated with a reduced capacity for endogenous neurosteroidogenesis and the relationship with behavioral outcomes. We demonstrated that mice directly subjected to a threat (foot shocks) and those witnessing the threat have decreased plasma levels of allopregnanolone. The expression of a key enzyme involved in endogenous neurosteroid synthesis, 5α-reductase type 2, is decreased in the basolateral amygdala, which is a major emotional processing hub implicated in PTSD. We demonstrated that genetic knockdown or pharmacological inhibition of 5α-reductase type 2 exaggerates the behavioral expression of fear in response to witnessed trauma, whereas oral treatment with an exogenous, synthetic neuroactive steroid gamma-aminobutyric acid-A receptor positive allosteric modulator with molecular pharmacology similar to allopregnanolone (SGE-516 [tool compound]) decreased the behavioral response to observational fear. These data implicate impaired endogenous neurosteroidogenesis in the pathophysiology of threat exposure, both direct and witnessed. Further, these data suggest that treatment with exogenous 5α-reduced neurosteroids or targeting endogenous neurosteroidogenesis may be beneficial for the treatment of individuals with PTSD, whether resulting from direct or witnessed trauma.
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Affiliation(s)
- Aidan Evans-Strong
- Neuroscience Department, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Najah Walton
- Neuroscience Department, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Katrina Blandino
- Neuroscience Department, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Abigail T C Roper
- Developmental and Brain Sciences Program, Department of Psychology, University of Massachusetts Boston, Boston, Massachusetts, USA
| | - S Tiffany Donaldson
- Developmental and Brain Sciences Program, Department of Psychology, University of Massachusetts Boston, Boston, Massachusetts, USA
| | - Mike Lewis
- Sage Therapeutics, Inc, Cambridge, Massachusetts, USA
| | - Jamie Maguire
- Neuroscience Department, Tufts University School of Medicine, Boston, Massachusetts, USA
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Peltier MR, Verplaetse TL, Altemus M, Zakiniaeiz Y, Ralevski EA, Mineur YS, Gueorguieva R, Picciotto MR, Cosgrove KP, Petrakis I, McKee SA. The role of neurosteroids in posttraumatic stress disorder and alcohol use disorder: A review of 10 years of clinical literature and treatment implications. Front Neuroendocrinol 2024; 73:101119. [PMID: 38184208 PMCID: PMC11185997 DOI: 10.1016/j.yfrne.2023.101119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 12/08/2023] [Accepted: 12/31/2023] [Indexed: 01/08/2024]
Abstract
Rates of alcohol use disorder (AUD) are increasing in men and women and there are high rates of concurrent posttraumatic stress disorder (PTSD) and AUD. AUD and PTSD synergistically increase symptomatology and negatively affect treatment outcomes; however, there are very limited pharmacological treatments for PTSD/AUD. Neurosteroids have been implicated in the underlying neurobiological mechanisms of both PTSD and AUD and may be a target for treatment development. This review details the past ten years of research on pregnenolone, progesterone, allopregnanolone, pregnanolone, estradiol, testosterone and dehydroepiandrosterone/dehydroepiandrosterone-sulfate (DHEA/DHEA-S) in the context of PTSD and AUD, including examination of trauma/alcohol-related variables, such as stress-reactivity. Emerging evidence that exogenous pregnenolone, progesterone, and allopregnanolone may be promising, novel interventions is also discussed. Specific emphasis is placed on examining the application of sex as a biological variable in this body of literature, given that women are more susceptible to both PTSD diagnoses and stress-related alcohol consumption.
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Affiliation(s)
- MacKenzie R Peltier
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA; VA Connecticut Healthcare System, Mental Health Service, West Haven, CT 06516, USA; National Center for PTSD, Clinical Neuroscience Division, West Haven, CT 06516, USA.
| | | | - Margaret Altemus
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA; VA Connecticut Healthcare System, Mental Health Service, West Haven, CT 06516, USA
| | - Yasmin Zakiniaeiz
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA
| | - Elizabeth A Ralevski
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA; VA Connecticut Healthcare System, Mental Health Service, West Haven, CT 06516, USA
| | - Yann S Mineur
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA
| | - Ralitza Gueorguieva
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA; Department of Biostatistics, School of Public Health, Yale University, New Haven, CT, USA
| | - Marina R Picciotto
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA
| | - Kelly P Cosgrove
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA; National Center for PTSD, Clinical Neuroscience Division, West Haven, CT 06516, USA; Department of Radiology and Biomedical Imaging, School of Medicine, Yale University, New Haven, CT, USA
| | - Ismene Petrakis
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA; VA Connecticut Healthcare System, Mental Health Service, West Haven, CT 06516, USA; National Center for PTSD, Clinical Neuroscience Division, West Haven, CT 06516, USA
| | - Sherry A McKee
- Yale School of Medicine, Department of Psychiatry, New Haven, CT 06519, USA
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Giatti S, Diviccaro S, Cioffi L, Cosimo Melcangi R. Post-Finasteride Syndrome And Post-Ssri Sexual Dysfunction: Two Clinical Conditions Apparently Distant, But Very Close. Front Neuroendocrinol 2024; 72:101114. [PMID: 37993021 DOI: 10.1016/j.yfrne.2023.101114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/31/2023] [Accepted: 11/19/2023] [Indexed: 11/24/2023]
Abstract
Post-finasteride syndrome and post-SSRI sexual dysfunction, are two poorly explored clinical conditions in which men treated for androgenetic alopecia with finasteride or for depression with SSRI antidepressants show persistent side effects despite drug suspension (e.g., sexual dysfunction, psychological complaints, sleep disorders). Because of some similarities in the symptoms, common pathological mechanisms are proposed here. Indeed, as discussed, clinical studies and preclinical data obtained so far suggest an important role for brain modulators (i.e., neuroactive steroids), neurotransmitters (i.e., serotonin, and cathecolamines), and gut microbiota in the context of the gut-brain axis. In particular, the observed interconnections of these signals in these two clinical conditions may suggest similar etiopathogenetic mechanisms, such as the involvement of the enzyme converting norepinephrine into epinephrine (i.e., phenylethanolamine N-methyltransferase). However, despite the current efforts, more work is still needed to advance the understanding of these clinical conditions in terms of diagnostic markers and therapeutic strategies.
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Affiliation(s)
- Silvia Giatti
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - Silvia Diviccaro
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - Lucia Cioffi
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - Roberto Cosimo Melcangi
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
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Marecki R, Kałuska J, Kolanek A, Hakało D, Waszkiewicz N. Zuranolone - synthetic neurosteroid in treatment of mental disorders: narrative review. Front Psychiatry 2023; 14:1298359. [PMID: 38116383 PMCID: PMC10729607 DOI: 10.3389/fpsyt.2023.1298359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 11/13/2023] [Indexed: 12/21/2023] Open
Abstract
With each passing year, the number of people suffering from mental disorders grows at a disturbing speed. Neuroactive steroids are a new promising group of drugs with the potential for use in many diseases like postpartum depression, postnatal psychosis, major depression, insomnia, bipolar disorder, and Parkinson's tremor, due to their ability to modulate the activity of GABAA receptor. Neurosteroids are progesterone metabolites that are synthesized from cholesterol or steroid hormones in various brain regions. They regulate neuronal development, regeneration, and neurotransmission. They are implicated in mood disorders, anxiety disorders, schizophrenia, PTSD, and impulsive aggression. Neurosteroids have been studied for their potential to prevent or treat neurodegenerative diseases such as Alzheimer's disease and HIV-associated dementia. They can promote neurogenesis, neuronal survival, myelination, and memory function. They can also affect the growth and sensitivity of hormone-dependent brain tumors such as gliomas. Zuranolone, a newly registered neurosteroid drug has shown huge flexibility in both clinical and ambulatory treatment thanks to its pharmacokinetic traits, especially the possibility for oral administration, unlike its predecessor Brexanolone. Zuranolone is a synthetic positive allosteric modulator of the GABAA receptor that can be taken orally. The review aims to summarize the current knowledge on zuranolone as a novel neurosteroid drug for various mental disorders, especially for postpartum mental disorders for which this drug was meant originally. It covers studies indexed in the PubMed, Scopus, and Web of Science databases published since 2017. Keywords used in the search, as well as inclusion and exclusion criteria, are given in the aims and methodology section. The review explains the evidence for the role of neurosteroids, especially allopregnanolone, in the pathophysiology and treatment of postpartum depression. It discusses the mechanisms of neurosteroid action, the changes in neurosteroid levels during pregnancy and postpartum, and the clinical trials of brexanolone and zuranolone, two synthetic analogs of allopregnanolone, for postpartum depression. It provides an overview of the biosynthesis and metabolism of neurosteroids in the central and peripheral nervous system. Furthermore, it explains the different sources and pathways of neurosteroid production and the factors that influence their synthesis and regulation, such as stress, hormones, drugs, and genetic variations. The review also explores the potential relevance of neurosteroids for other psychiatric disorders, such as major depression, bipolar disorder, post-traumatic stress disorder (PTSD), schizophrenia, and premenstrual dysphoric disorder. Finally, it highlights the associations between neurosteroid levels and symptom severity and the effects of neurosteroid modulation on mood, cognition, and neuroplasticity.
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Lin YW, Tu YK, Hung KC, Liang CS, Tseng PT, Lin PY, Chia-Cheng Lai E, Hsu CW. Efficacy and safety of zuranolone in major depressive disorder: a meta-analysis of factor effect and dose-response analyses. EClinicalMedicine 2023; 66:102308. [PMID: 38045802 PMCID: PMC10690540 DOI: 10.1016/j.eclinm.2023.102308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 10/18/2023] [Accepted: 10/26/2023] [Indexed: 12/05/2023] Open
Abstract
Background Zuranolone is recognised as a promising antidepressant agent. Our study aimed to investigate the efficacy and safety of zuranolone in treating major depressive disorder (MDD). Methods A systematic review was conducted by searching major databases from inception to August 20, 2023 (INPLASY: 202360087). A meta-analysis was performed by using a random-effects model to calculate effect sizes, expressed as standardised mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs). The primary outcome was improvement in depressive symptoms, while secondary outcomes included response and remission rates of depression, improvement in anxiety symptoms, incidence of dropouts, and any side effects. We conducted subgroup analyses for general MDD and postpartum-onset MDD and a dose-response meta-analysis to estimate the relationship between zuranolone dose and outcomes. Findings The study included seven randomised control trials involving 1789 patients. Zuranolone reduced depressive symptoms (SMD = -0.37, 95% CIs = -0.51 to -0.23), increased response rate (OR = 2.06, 95% CIs = 1.48-2.85) and remission rate (OR = 2.04, 95% CIs = 1.38-3.02), and reduced anxiety symptoms (SMD = -0.26, 95% CIs = -0.39 to -0.14). Furthermore, zuranolone-treated patients experienced more side effects than those in the control group (OR = 1.40, 95% CIs = 1.10-1.78), although dropout rate did not significantly differ between the two groups (OR = 1.13, 95% CIs = 0.85-1.49). According to the dose-response meta-analysis, zuranolone could effectively improve depression and anxiety at increasing doses up to a maximum daily dose of 30 mg; however, side effects increased with doses exceeding 30 mg. Based on subgroup analyses, zuranolone showed greater efficacy in treatment of postpartum-onset MDD than general MDD, but the difference did not reach statistical significance. Interpretation Our findings suggested that zuranolone is effective in alleviating depression and anxiety. Nevertheless, there is a potential risk of adverse effects. Given its therapeutic efficacy and risk of side effects, a daily dose of 30 mg appears to be the optimal choice. Funding Chang Gung Medical Foundation.
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Affiliation(s)
- Yu-Wei Lin
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yu-Kang Tu
- Institute of Health Data Analytics & Statistics, College of Public Health, National Taiwan University, Taipei, Taiwan
- Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
| | - Kuo-Chuan Hung
- Department of Anesthesiology, Chi Mei Medical Center, Tainan, Taiwan
| | - Chih-Sung Liang
- Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Department of Psychiatry, National Defense Medical Center, Taipei, Taiwan
| | - Ping-Tao Tseng
- Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
- Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan
- Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung City, Taiwan
| | - Pao-Yen Lin
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Edward Chia-Cheng Lai
- School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Wei Hsu
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Pillerová M, Pastorek M, Borbélyová V, Riljak V, Frick KM, Hodosy J, Tóthová L. Sex steroid hormones in depressive disorders as a basis for new potential treatment strategies. Physiol Res 2022; 71:S187-S202. [PMID: 36647907 PMCID: PMC9906660 DOI: 10.33549/physiolres.935001] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 10/17/2022] [Indexed: 01/25/2023] Open
Abstract
The sex steroid hormones (SSHs) such as testosterone, estradiol, progesterone, and their metabolites have important organizational and activational impacts on the brain during critical periods of brain development and in adulthood. A variety of slow and rapid mechanisms mediate both organizational and activational processes via intracellular or membrane receptors for SSHs. Physiological concentrations and distribution of SSHs in the brain result in normal brain development. Nevertheless, dysregulation of hormonal equilibrium may result in several mood disorders, including depressive disorders, later in adolescence or adulthood. Gender differences in cognitive abilities, emotions as well as the 2-3 times higher prevalence of depressive disorders in females, were already described. This implies that SSHs may play a role in the development of depressive disorders. In this review, we discuss preclinical and clinical studies linked to SSHs and development of depressive disorders. Our secondary aim includes a review of up-to-date knowledge about molecular mechanisms in the pathogenesis of depressive disorders. Understanding these molecular mechanisms might lead to significant treatment adjustments for patients with depressive disorders and to an amelioration of clinical outcomes for these patients. Nevertheless, the impact of SSHs on the brain in the context of the development of depressive disorders, progression, and treatment responsiveness is complex in nature, and depends upon several factors in concert such as gender, age, comorbidities, and general health conditions.
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Affiliation(s)
- M Pillerová
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovak Republic.
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10
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Wang YM, Xia CY, Jia HM, He J, Lian WW, Yan Y, Wang WP, Zhang WK, Xu JK. Sigma-1 receptor: A potential target for the development of antidepressants. Neurochem Int 2022; 159:105390. [PMID: 35810915 DOI: 10.1016/j.neuint.2022.105390] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 06/10/2022] [Accepted: 07/05/2022] [Indexed: 10/17/2022]
Abstract
Though a great many of studies on the development of antidepressants for the therapy of major depression disorder (MDD) and the development of antidepressants have been carried out, there still lacks an efficient approach in clinical practice. The involvement of Sigma-1 receptor in the pathological process of MDD has been verified. In this review, recent research focusing on the role of Sigma-1 receptor in the etiology of MDD were summarized. Preclinical studies and clinical trials have found that stress induce the variation of Sigma-1 receptor in the blood, brain and heart. Dysfunction and absence of Sigma-1 receptor result in depressive-like behaviors in rodent animals. Agonists of Sigma-1 receptor show not only antidepressant-like activities but also therapeutical effects in complications of depression. The mechanisms underlying antidepressant-like effects of Sigma-1 receptor may include suppressing neuroinflammation, regulating neurotransmitters, ameliorating brain-derived neurotrophic factor and N-Methyl-D-Aspartate receptor, and alleviating the endoplasmic reticulum stress and mitochondria damage during stress. Therefore, Sigma-1 receptor represents a potential target for antidepressants development.
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Affiliation(s)
- Yu-Ming Wang
- School of Life Sciences & School of Chinese Medicine Sciences, Beijing University of Chinese Medicine, Beijing, 100029, PR China; Institute of Clinical Medical Sciences & Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, PR China
| | - Cong-Yuan Xia
- Institute of Clinical Medical Sciences & Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, PR China
| | - Hong-Mei Jia
- Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, PR China
| | - Jun He
- Institute of Clinical Medical Sciences & Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, PR China
| | - Wen-Wen Lian
- Institute of Clinical Medical Sciences & Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, PR China
| | - Yu Yan
- Institute of Clinical Medical Sciences & Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, PR China
| | - Wen-Ping Wang
- Institute of Clinical Medical Sciences & Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, PR China
| | - Wei-Ku Zhang
- Institute of Clinical Medical Sciences & Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, PR China.
| | - Jie-Kun Xu
- School of Life Sciences & School of Chinese Medicine Sciences, Beijing University of Chinese Medicine, Beijing, 100029, PR China.
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11
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Shi Z, Liang X, Zhao Y, Liu W, Martyniuk CJ. Neurotoxic effects of synthetic phenolic antioxidants on dopaminergic, serotoninergic, and GABAergic signaling in larval zebrafish (Danio rerio). THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 830:154688. [PMID: 35318061 DOI: 10.1016/j.scitotenv.2022.154688] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/15/2022] [Accepted: 03/15/2022] [Indexed: 05/14/2023]
Abstract
Synthetic phenolic antioxidants (SPAs) are an environmental concern because they are widely detected in aquatic ecosystems and can pose potential threats to organisms. Studies have reported developmental deficits and behavioral changes in response to SPAs, indicating possible neurotoxic effects. However, their neuroactive potency as well as their mode of action (MoA) remain unclear. As such, this study evaluated the potential neurotoxicity of three SPAs [butylated hydroxytoluene (BHT), 2,4-di-tert-butylphenol (2,4-DTBP), and 4-tert-octylphenol (4-t-OP)] at three concentrations (0.01, 0.1 and 1 μM) to zebrafish larvae. Both 2,4-DTBP and BHT decreased spontaneous tail coiling (STC) at 28 hpf (hours post fertilization) whereas 4-t-OP increased STC. Locomotor activity, based on the velocity and distance of larvae (144 hpf) travelled, was promoted by 2,4-DTBP while it decreased in larvae with exposure to 4-t-OP and BHT. In the light-dark preference assay, exposure to either 2,4-DTBP or BHT resulted in variability in the visiting frequency to the dark zone, and larvae (144 hpf) spent less time in the dark, suggesting anxiety-like behavior. Conversely, zebrafish exposed to 4-t-OP, especially at 1 μM concentration, were hypoactive and spent more time in dark, suggestive of anxiolytic-like responses. RNA-seq was conducted to discern mechanisms underlying behavioral responses. Transcriptomic analysis revealed that gene networks related to neuroactive ligand-receptor interaction as well as neurotransmitter-related pathways were altered by all three SPAs based on gene set and subnetwork enrichment analysis. Modulation of dopaminergic, serotoninergic, and/or GABAergic signaling at the transcript level was noted for each of the three SPAs, but different expression patterns were observed, indicating SPA- and dose-specific responses of the transcriptome. The present study provides novel insight into potential mechanisms associated with neurotoxicity of SPAs congeners.
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Affiliation(s)
- Ziyue Shi
- Inner Mongolia Key Laboratory of Environmental Pollution Control & Waste Resource Reuse, School of Ecology and Environment, Inner Mongolia University, Hohhot 010021, China
| | - Xuefang Liang
- Inner Mongolia Key Laboratory of Environmental Pollution Control & Waste Resource Reuse, School of Ecology and Environment, Inner Mongolia University, Hohhot 010021, China.
| | - Yaqian Zhao
- Inner Mongolia Key Laboratory of Environmental Pollution Control & Waste Resource Reuse, School of Ecology and Environment, Inner Mongolia University, Hohhot 010021, China
| | - Wang Liu
- Inner Mongolia Key Laboratory of Environmental Pollution Control & Waste Resource Reuse, School of Ecology and Environment, Inner Mongolia University, Hohhot 010021, China
| | - Christopher J Martyniuk
- Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida Genetics Institute, Interdisciplinary Program in Biomedical Sciences Neuroscience, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611, USA
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12
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Lambert PM, Lu X, Zorumski CF, Mennerick S. Physiological markers of rapid antidepressant effects of allopregnanolone. J Neuroendocrinol 2022; 34:e13023. [PMID: 34423498 PMCID: PMC8807818 DOI: 10.1111/jne.13023] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 02/04/2023]
Abstract
The rise of ketamine and brexanolone as rapid antidepressant treatments raises the question of common mechanisms. Both drugs act without the long onset time of traditional antidepressants such as selective serotonin reuptake inhibitors. The drugs also share the interesting feature of benefit that persists beyond the initial drug lifetime. Here, we briefly review literature on functional changes that may mark the triggering mechanism of rapid antidepressant actions. Because ketamine has a longer history of study as a rapid antidepressant, we use this literature as a template to guide hypotheses about common action. Brexanolone has the complication of being a formulation of a naturally occurring neurosteroid; thus, endogenous levels need to be considered when studying the impact of exogenous administration. We conclude that network disinhibition and increased high-frequency oscillations are candidates to mediate acute triggering effects of rapid antidepressants.
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Affiliation(s)
- Peter M Lambert
- Department of Psychiatry, Washington University in St Louis School of Medicine, St Louis, MO, USA
| | - Xinguo Lu
- Department of Psychiatry, Washington University in St Louis School of Medicine, St Louis, MO, USA
| | - Charles F Zorumski
- Department of Psychiatry, Washington University in St Louis School of Medicine, St Louis, MO, USA
- Taylor Family Institute for Innovative Psychiatric Research, Washington University in St Louis School of Medicine, St Louis, MO, USA
| | - Steven Mennerick
- Department of Psychiatry, Washington University in St Louis School of Medicine, St Louis, MO, USA
- Taylor Family Institute for Innovative Psychiatric Research, Washington University in St Louis School of Medicine, St Louis, MO, USA
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13
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Pillerová M, Borbélyová V, Pastorek M, Riljak V, Hodosy J, Frick KM, Tóthová L. Molecular actions of sex hormones in the brain and their potential treatment use in anxiety disorders. Front Psychiatry 2022; 13:972158. [PMID: 36159923 PMCID: PMC9492942 DOI: 10.3389/fpsyt.2022.972158] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/17/2022] [Indexed: 11/13/2022] Open
Abstract
Anxiety disorders are one of the most prevalent mood disorders that can lead to impaired quality of life. Current treatment of anxiety disorders has various adverse effects, safety concerns, or restricted efficacy; therefore, novel therapeutic targets need to be studied. Sex steroid hormones (SSHs) play a crucial role in the formation of brain structures, including regions of the limbic system and prefrontal cortex during perinatal development. In the brain, SSHs have activational and organizational effects mediated by either intracellular or transmembrane G-protein coupled receptors. During perinatal developmental periods, the physiological concentrations of SSHs lead to the normal development of the brain; however, the early hormonal dysregulation could result in various anxiety diorders later in life. Sex differences in the prevalence of anxiety disorders suggest that SSHs might be implicated in their development. In this review, we discuss preclinical and clinical studies regarding the role of dysregulated SSHs signaling during early brain development that modifies the risk for anxiety disorders in a sex-specific manner in adulthood. Moreover, our aim is to summarize potential molecular mechanisms by which the SSHs may affect anxiety disorders in preclinical research. Finally, the potential effects of SSHs in the treatment of anxiety disorders are discussed.
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Affiliation(s)
- Miriam Pillerová
- Faculty of Medicine, Institute of Molecular Biomedicine, Comenius University in Bratislava, Bratislava, Slovakia
| | - Veronika Borbélyová
- Faculty of Medicine, Institute of Molecular Biomedicine, Comenius University in Bratislava, Bratislava, Slovakia
| | - Michal Pastorek
- Faculty of Medicine, Institute of Molecular Biomedicine, Comenius University in Bratislava, Bratislava, Slovakia
| | - Vladimír Riljak
- First Faculty of Medicine, Institute of Physiology, Charles University, Prague, Czechia
| | - Július Hodosy
- Faculty of Medicine, Institute of Molecular Biomedicine, Comenius University in Bratislava, Bratislava, Slovakia
| | - Karyn M Frick
- Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, United States
| | - L'ubomíra Tóthová
- Faculty of Medicine, Institute of Molecular Biomedicine, Comenius University in Bratislava, Bratislava, Slovakia
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14
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Mitra S, Bult-Ito A. Bidirectional Behavioral Selection in Mice: A Novel Pre-clinical Approach to Examining Compulsivity. Front Psychiatry 2021; 12:716619. [PMID: 34566718 PMCID: PMC8458042 DOI: 10.3389/fpsyt.2021.716619] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 08/16/2021] [Indexed: 11/17/2022] Open
Abstract
Obsessive-compulsive disorder (OCD) and related disorders (OCRD) is one of the most prevalent neuropsychiatric disorders with no definitive etiology. The pathophysiological attributes of OCD are driven by a multitude of factors that involve polygenic mechanisms, gender, neurochemistry, physiological status, environmental exposures and complex interactions among these factors. Such complex intertwining of contributing factors imparts clinical heterogeneity to the disorder making it challenging for therapeutic intervention. Mouse strains selected for excessive levels of nest- building behavior exhibit a spontaneous, stable and predictable compulsive-like behavioral phenotype. These compulsive-like mice exhibit heterogeneity in expression of compulsive-like and other adjunct behaviors that might serve as a valuable animal equivalent for examining the interactions of genetics, sex and environmental factors in influencing the pathophysiology of OCD. The current review summarizes the existing findings on the compulsive-like mice that bolster their face, construct and predictive validity for studying various dimensions of compulsive and associated behaviors often reported in clinical OCD and OCRD.
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Affiliation(s)
- Swarup Mitra
- Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, NY, United States
| | - Abel Bult-Ito
- Department of Biology and Wildlife, University of Alaska Fairbanks, Fairbanks, AK, United States
- OCRD Biomed LLC, Fairbanks, AK, United States
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15
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Zhu Y, Wu X, Zhou R, Sie O, Niu Z, Wang F, Fang Y. Hypothalamic-Pituitary-End-Organ Axes: Hormone Function in Female Patients with Major Depressive Disorder. Neurosci Bull 2021; 37:1176-1187. [PMID: 33909242 DOI: 10.1007/s12264-021-00689-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 11/27/2020] [Indexed: 12/27/2022] Open
Abstract
Classic hypothalamic-pituitary-end-organ feedback loops - the hypothalamic-pituitary-adrenal axis (HPAA), hypothalamic-pituitary-thyroidal axis (HPTA), and hypothalamic-pituitary-gonadal axis (HPGA) - are associated with the neuroendocrine and immune systems in major depressive disorder (MDD). Female patients with MDD present with evident neuroendocrine and immunological changes. Glucocorticoid, thyroid hormone, and reproductive steroid levels fluctuate with menstrual cycles, which might lead to glucocorticoid receptor resistance, impairment of triiodothyronine conversion, and sex hormone secretion disorders. In this review, we summarize the independent and interactive functions of these three axes in female MDD patients. The similar molecular structure of steroids implies an interrelationship between the hypothalamic-pituitary-end-organ axes and the competitive inhibitory effects at the receptor level, especially when considering the HPAA and HPGA.
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Affiliation(s)
- Yuncheng Zhu
- Division of Mood Disorders, Shanghai Hongkou Mental Health Center, Shanghai, 200083, China.,Clinical Research Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Xiaohui Wu
- Clinical Research Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Rubai Zhou
- Clinical Research Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Oliver Sie
- Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Zhiang Niu
- Clinical Research Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
| | - Fang Wang
- Shanghai Yangpu Mental Health Center, Shanghai, 200093, China.
| | - Yiru Fang
- Clinical Research Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China. .,CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai, 200031, China. .,Shanghai Key Laboratory of Psychotic Disorders, Shanghai, 201108, China.
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16
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Gliozzi M, Musolino V, Bosco F, Scicchitano M, Scarano F, Nucera S, Zito MC, Ruga S, Carresi C, Macrì R, Guarnieri L, Maiuolo J, Tavernese A, Coppoletta AR, Nicita C, Mollace R, Palma E, Muscoli C, Belzung C, Mollace V. Cholesterol homeostasis: Researching a dialogue between the brain and peripheral tissues. Pharmacol Res 2020; 163:105215. [PMID: 33007421 DOI: 10.1016/j.phrs.2020.105215] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/23/2020] [Accepted: 09/24/2020] [Indexed: 02/07/2023]
Abstract
Cholesterol homeostasis is a highly regulated process in human body because of its several functions underlying the biology of cell membranes, the synthesis of all steroid hormones and bile acids and the need of trafficking lipids destined to cell metabolism. In particular, it has been recognized that peripheral and central nervous system cholesterol metabolism are separated by the blood brain barrier and are regulated independently; indeed, peripherally, it depends on the balance between dietary intake and hepatic synthesis on one hand and its degradation on the other, whereas in central nervous system it is synthetized de novo to ensure brain physiology. In view of this complex metabolism and its relevant functions in mammalian, impaired levels of cholesterol can induce severe cellular dysfunction leading to metabolic, cardiovascular and neurodegenerative diseases. The aim of this review is to clarify the role of cholesterol homeostasis in health and disease highlighting new intriguing aspects of the cross talk between its central and peripheral metabolism.
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Affiliation(s)
- Micaela Gliozzi
- Institute of Research for Food Safety & Health (IRC-FSH) - Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
| | - Vincenzo Musolino
- Institute of Research for Food Safety & Health (IRC-FSH) - Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
| | - Francesca Bosco
- Institute of Research for Food Safety & Health (IRC-FSH) - Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
| | - Miriam Scicchitano
- Institute of Research for Food Safety & Health (IRC-FSH) - Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
| | - Federica Scarano
- Institute of Research for Food Safety & Health (IRC-FSH) - Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
| | - Saverio Nucera
- Institute of Research for Food Safety & Health (IRC-FSH) - Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
| | - Maria Caterina Zito
- Institute of Research for Food Safety & Health (IRC-FSH) - Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
| | - Stefano Ruga
- Institute of Research for Food Safety & Health (IRC-FSH) - Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
| | - Cristina Carresi
- Institute of Research for Food Safety & Health (IRC-FSH) - Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
| | - Roberta Macrì
- Institute of Research for Food Safety & Health (IRC-FSH) - Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
| | - Lorenza Guarnieri
- Institute of Research for Food Safety & Health (IRC-FSH) - Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
| | - Jessica Maiuolo
- Institute of Research for Food Safety & Health (IRC-FSH) - Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
| | - Annamaria Tavernese
- Division of Cardiology, University Hospital Policlinico Tor Vergata, Rome, Italy.
| | - Anna Rita Coppoletta
- Institute of Research for Food Safety & Health (IRC-FSH) - Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
| | - Caterina Nicita
- Institute of Research for Food Safety & Health (IRC-FSH) - Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
| | - Rocco Mollace
- Institute of Research for Food Safety & Health (IRC-FSH) - Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
| | - Ernesto Palma
- Institute of Research for Food Safety & Health (IRC-FSH) - Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
| | - Carolina Muscoli
- Institute of Research for Food Safety & Health (IRC-FSH) - Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy; IRCCS San Raffaele Pisana, Via di Valcannuta, Rome, Italy.
| | | | - Vincenzo Mollace
- Institute of Research for Food Safety & Health (IRC-FSH) - Department of Health Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy; IRCCS San Raffaele Pisana, Via di Valcannuta, Rome, Italy.
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17
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Synthesis and Structure—Activity (Anxiolytic) Relationship Analysis of Leucyltryptophan Ligands of 18-KDA Translocator Protein. Pharm Chem J 2020. [DOI: 10.1007/s11094-020-02241-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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18
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Bianchi VE, Rizzi L, Bresciani E, Omeljaniuk RJ, Torsello A. Androgen Therapy in Neurodegenerative Diseases. J Endocr Soc 2020; 4:bvaa120. [PMID: 33094209 PMCID: PMC7568521 DOI: 10.1210/jendso/bvaa120] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 08/18/2020] [Indexed: 12/14/2022] Open
Abstract
Neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington disease, are characterized by the loss of neurons as well as neuronal function in multiple regions of the central and peripheral nervous systems. Several studies in animal models have shown that androgens have neuroprotective effects in the brain and stimulate axonal regeneration. The presence of neuronal androgen receptors in the peripheral and central nervous system suggests that androgen therapy might be useful in the treatment of neurodegenerative diseases. To illustrate, androgen therapy reduced inflammation, amyloid-β deposition, and cognitive impairment in patients with AD. As well, improvements in remyelination in MS have been reported; by comparison, only variable results are observed in androgen treatment of PD. In ALS, androgen administration stimulated motoneuron recovery from progressive damage and regenerated both axons and dendrites. Only a few clinical studies are available in human individuals despite the safety and low cost of androgen therapy. Clinical evaluations of the effects of androgen therapy on these devastating diseases using large populations of patients are strongly needed.
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Affiliation(s)
- Vittorio Emanuele Bianchi
- Department of Endocrinology and Metabolism, Clinical Center Stella Maris, Strada Rovereta, Falciano, San Marino
| | - Laura Rizzi
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Elena Bresciani
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | | | - Antonio Torsello
- School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
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19
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Pinna G. Allopregnanolone (1938-2019): A trajectory of 80 years of outstanding scientific achievements. Neurobiol Stress 2020; 13:100246. [PMID: 32875009 PMCID: PMC7451447 DOI: 10.1016/j.ynstr.2020.100246] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Affiliation(s)
- Graziano Pinna
- The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, 1601 W. Taylor Street, Chicago, IL, 60612, USA
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20
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Yu EJ, Yamaguchi T, Lee JH, Lim AR, Lee JH, Park H, Oh TJ. Enzymatic Synthesis of Anabolic Steroid Glycosides by Glucosyltransferase from Terribacillus sp. PAMC 23288. J Microbiol Biotechnol 2020; 30:604-614. [PMID: 31893610 PMCID: PMC9728329 DOI: 10.4014/jmb.1911.11057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The application of steroids has steadily increased thanks to their therapeutic effects. However, alternatives are required due their severe side effects; thus, studies on the activities of steroid derivatives are underway. Sugar derivatives of nandrolone, which is used to treat breast cancer, as well as cortisone and prednisone, which reduce inflammation, pain, and edema, are unknown. We linked O-glucose to nandrolone and testosterone using UDP-glucosyltransferase (UGT-1) and, then, tested their bioactivities in vitro. Analysis by NMR showed that the derivatives were 17β-nandrolone β-D-glucose and 17β-testosterone β-D-glucose, respectively. The viability was higher and cytotoxicity was evident in PC12 cells incubated with rotenone and, testosterone derivatives, compared to the controls. SH-SY5Y cells incubated with H2O2 and nandrolone derivatives remained viable and cytotoxicity was attenuated. Both derivatives enhanced neuronal protective effects and increased the amounts of cellular ATP.
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Affiliation(s)
- Eun-Ji Yu
- Department of Life Science and Biochemical Engineering, SunMoon University, Asan 31460, Republic of Korea
| | - Tokutaro Yamaguchi
- Department of Life Science and Biochemical Engineering, SunMoon University, Asan 31460, Republic of Korea,Department of Pharmaceutical Engineering and Biotechnology, SunMoon University, Asan 31460, Republic of Korea,Genome-Based BioIT Convergence Institute, Asan 31460, Republic of Korea
| | - Joo-Ho Lee
- Genome-Based BioIT Convergence Institute, Asan 31460, Republic of Korea
| | - A-Rang Lim
- Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea
| | - Jun Hyuck Lee
- Unit of Research for Practical Application, Korea Polar Research Institute, Incheon 21990, Republic of Korea,Department of Polar Sciences, University of Science and Technology, Incheon 21990, Republic of Korea
| | - Hyun Park
- Division of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, Republic of Korea,Corresponding authors H.P. Phone: +82 2 3290 3051 E-mail: T.-J.O. Phone: +82 41 530 2677 E-mail:
| | - Tae-Jin Oh
- Department of Life Science and Biochemical Engineering, SunMoon University, Asan 31460, Republic of Korea,Department of Pharmaceutical Engineering and Biotechnology, SunMoon University, Asan 31460, Republic of Korea,Genome-Based BioIT Convergence Institute, Asan 31460, Republic of Korea,Corresponding authors H.P. Phone: +82 2 3290 3051 E-mail: T.-J.O. Phone: +82 41 530 2677 E-mail:
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21
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Almeida FB, Nin MS, Barros HMT. The role of allopregnanolone in depressive-like behaviors: Focus on neurotrophic proteins. Neurobiol Stress 2020; 12:100218. [PMID: 32435667 PMCID: PMC7231971 DOI: 10.1016/j.ynstr.2020.100218] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 03/16/2020] [Accepted: 03/30/2020] [Indexed: 12/18/2022] Open
Abstract
Allopregnanolone (3α,5α-tetrahydroprogesterone; pharmaceutical formulation: brexanolone) is a neurosteroid that has recently been approved for the treatment of postpartum depression, promising to fill part of a long-lasting gap in the effectiveness of pharmacotherapies for depressive disorders. In this review, we explore the experimental research that characterized the antidepressant-like effects of allopregnanolone, with a particular focus on the neurotrophic adaptations induced by this neurosteroid in preclinical studies. We demonstrate that there is a consistent decrease in allopregnanolone levels in limbic brain areas in rodents submitted to stress-induced models of depression, such as social isolation and chronic unpredictable stress. Further, both the drug-induced upregulation of allopregnanolone or its direct administration reduce depressive-like behaviors in models such as the forced swim test. The main drugs of interest that upregulate allopregnanolone levels are selective serotonin reuptake inhibitors (SSRIs), which present the neurosteroidogenic property even in lower, non-SSRI doses. Finally, we explore how these antidepressant-like behaviors are related to neurogenesis, particularly in the hippocampus. The protagonist in this mechanism is likely the brain-derived neurotrophic factor (BFNF), which is decreased in animal models of depression and may be restored by the normalization of allopregnanolone levels. The role of an interaction between GABA and the neurotrophic mechanisms needs to be further investigated.
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Key Words
- 3α,5α-tetrahydroprogesterone
- BDNF
- BDNF, brain-derived neurotrophic factor
- Brexanolone
- CSF, cerebrospinal fluid
- CUS, chronic unpredictable stress
- Depression
- EKR, extracellular signal-regulated kinase
- FST, forced swim test
- GABA, γ-aminobutyric acid
- GABAAR, GABA type A receptor
- HSD, hydroxysteroid dehydrogenase
- NGF, nerve growth factor
- Neurosteroid
- PTSD, post-traumatic stress disorder
- PXR, pregnane xenobiotic receptor
- SBSS, selective brain steroidogenic stimulant
- SSRI, selective serotonin reuptake inhibitor
- Selective brain steroidogenic stimulant
- THP, tetrahydroprogesterone
- TSPO, 18 kDa translocator protein
- TrkB, tropomyosin receptor kinase B
- USV, ultrasonic vocalization
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Affiliation(s)
- Felipe Borges Almeida
- Graduate Program in Health Sciences: Pharmacology and Toxicology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), 90050-170, Porto Alegre, RS, Brazil
| | - Maurício Schüler Nin
- Graduate Program in Health Sciences: Pharmacology and Toxicology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), 90050-170, Porto Alegre, RS, Brazil.,Centro Universitário Metodista do IPA, 90420-060, Porto Alegre, RS, Brazil.,Graduate Program in Biological Sciences: Pharmacology and Therapeutics, Universidade Federal do Rio Grande do Sul (UFRGS), 90040-060, Porto Alegre, RS, Brazil
| | - Helena Maria Tannhauser Barros
- Graduate Program in Health Sciences: Pharmacology and Toxicology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), 90050-170, Porto Alegre, RS, Brazil
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22
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Paul SM, Pinna G, Guidotti A. Allopregnanolone: From molecular pathophysiology to therapeutics. A historical perspective. Neurobiol Stress 2020; 12:100215. [PMID: 32435665 PMCID: PMC7231972 DOI: 10.1016/j.ynstr.2020.100215] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 03/05/2020] [Accepted: 03/09/2020] [Indexed: 11/17/2022] Open
Abstract
Allopregnanolone is synthesized in the central nervous system either de novo from cholesterol or from steroid hormone precursors like progesterone and pregnenolone. Over the past 30 years, direct and rapid, non-genomic actions of allopregnanolone and its derivatives via GABAA receptors have been demonstrated. Changes in brain levels of allopregnanolone during pregnancy and in the postpartum period, or during exposure to protracted stress appear to play a crucial role in the pathophysiology of mood disorders. The discovery that allopregnanolone at low (nanomolar) concentrations elicits marked anxiolytic, anti-stress and antidepressant effects by facilitating allosterically the action of GABA at extrasynaptic GABAA receptors has provided new perspectives for the discovery of novel drugs useful for the treatment of mood disorders. These findings have led to the seminal clinical studies that recently demonstrated that treatment with allopregnanolone (i.e., brexanolone) can dramatically and rapidly improve the symptoms of postpartum depression in many patients.
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Affiliation(s)
- Steven M Paul
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.,The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA.,Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
| | - Graziano Pinna
- The Psychiatric Institute, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Alessandro Guidotti
- The Psychiatric Institute, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.,Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of IIIinois at Chicago, USA
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Abstract
Understanding the neurobiological basis of post-traumatic stress disorder (PTSD) is fundamental to accurately diagnose this neuropathology and offer appropriate treatment options to patients. The lack of pharmacological effects, too often observed with the most currently used drugs, the selective serotonin reuptake inhibitors (SSRIs), makes even more urgent the discovery of new pharmacological approaches. Reliable animal models of PTSD are difficult to establish because of the present limited understanding of the PTSD heterogeneity and of the influence of various environmental factors that trigger the disorder in humans. We summarize knowledge on the most frequently investigated animal models of PTSD, focusing on both their behavioral and neurobiological features. Most of them can reproduce not only behavioral endophenotypes, including anxiety-like behaviors or fear-related avoidance, but also neurobiological alterations, such as glucocorticoid receptor hypersensitivity or amygdala hyperactivity. Among the various models analyzed, we focus on the social isolation mouse model, which reproduces some deficits observed in humans with PTSD, such as abnormal neurosteroid biosynthesis, changes in GABAA receptor subunit expression and lack of pharmacological response to benzodiazepines. Neurosteroid biosynthesis and its interaction with the endocannabinoid system are altered in PTSD and are promising neuronal targets to discover novel PTSD agents. In this regard, we discuss pharmacological interventions and we highlight exciting new developments in the fields of research for novel reliable PTSD biomarkers that may enable precise diagnosis of the disorder and more successful pharmacological treatments for PTSD patients.
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Szechtman H, Harvey BH, Woody EZ, Hoffman KL. The Psychopharmacology of Obsessive-Compulsive Disorder: A Preclinical Roadmap. Pharmacol Rev 2020; 72:80-151. [PMID: 31826934 DOI: 10.1124/pr.119.017772] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
This review evaluates current knowledge about obsessive-compulsive disorder (OCD), with the goal of providing a roadmap for future directions in research on the psychopharmacology of the disorder. It first addresses issues in the description and diagnosis of OCD, including the structure, measurement, and appropriate description of the disorder and issues of differential diagnosis. Current pharmacotherapies for OCD are then reviewed, including monotherapy with serotonin reuptake inhibitors and augmentation with antipsychotic medication and with psychologic treatment. Neuromodulatory therapies for OCD are also described, including psychosurgery, deep brain stimulation, and noninvasive brain stimulation. Psychotherapies for OCD are then reviewed, focusing on behavior therapy, including exposure and response prevention and cognitive therapy, and the efficacy of these interventions is discussed, touching on issues such as the timing of sessions, the adjunctive role of pharmacotherapy, and the underlying mechanisms. Next, current research on the neurobiology of OCD is examined, including work probing the role of various neurotransmitters and other endogenous processes and etiology as clues to the neurobiological fault that may underlie OCD. A new perspective on preclinical research is advanced, using the Research Domain Criteria to propose an adaptationist viewpoint that regards OCD as the dysfunction of a normal motivational system. A systems-design approach introduces the security motivation system (SMS) theory of OCD as a framework for research. Finally, a new perspective on psychopharmacological research for OCD is advanced, exploring three approaches: boosting infrastructure facilities of the brain, facilitating psychotherapeutic relearning, and targeting specific pathways of the SMS network to fix deficient SMS shut-down processes. SIGNIFICANCE STATEMENT: A significant proportion of patients with obsessive-compulsive disorder (OCD) do not achieve remission with current treatments, indicating the need for innovations in psychopharmacology for the disorder. OCD may be conceptualized as the dysfunction of a normal, special motivation system that evolved to manage the prospect of potential danger. This perspective, together with a wide-ranging review of the literature, suggests novel directions for psychopharmacological research, including boosting support systems of the brain, facilitating relearning that occurs in psychotherapy, and targeting specific pathways in the brain that provide deficient stopping processes in OCD.
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Affiliation(s)
- Henry Szechtman
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada (H.S.); SAMRC Unit on Risk Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, and Center of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University (Potchefstroom Campus), Potchefstroom, South Africa (B.H.H.); Department of Psychology, University of Waterloo, Waterloo, Ontario, Canada (E.Z.W.); and Centro de Investigación en Reproducción Animal, CINVESTAV-Universidad Autónoma de Tlaxcala, Tlaxcala, Mexico (K.L.H.)
| | - Brian H Harvey
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada (H.S.); SAMRC Unit on Risk Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, and Center of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University (Potchefstroom Campus), Potchefstroom, South Africa (B.H.H.); Department of Psychology, University of Waterloo, Waterloo, Ontario, Canada (E.Z.W.); and Centro de Investigación en Reproducción Animal, CINVESTAV-Universidad Autónoma de Tlaxcala, Tlaxcala, Mexico (K.L.H.)
| | - Erik Z Woody
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada (H.S.); SAMRC Unit on Risk Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, and Center of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University (Potchefstroom Campus), Potchefstroom, South Africa (B.H.H.); Department of Psychology, University of Waterloo, Waterloo, Ontario, Canada (E.Z.W.); and Centro de Investigación en Reproducción Animal, CINVESTAV-Universidad Autónoma de Tlaxcala, Tlaxcala, Mexico (K.L.H.)
| | - Kurt Leroy Hoffman
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada (H.S.); SAMRC Unit on Risk Resilience in Mental Disorders, Department of Psychiatry, University of Cape Town, and Center of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University (Potchefstroom Campus), Potchefstroom, South Africa (B.H.H.); Department of Psychology, University of Waterloo, Waterloo, Ontario, Canada (E.Z.W.); and Centro de Investigación en Reproducción Animal, CINVESTAV-Universidad Autónoma de Tlaxcala, Tlaxcala, Mexico (K.L.H.)
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Belelli D, Hogenkamp D, Gee KW, Lambert JJ. Realising the therapeutic potential of neuroactive steroid modulators of the GABA A receptor. Neurobiol Stress 2019; 12:100207. [PMID: 32435660 PMCID: PMC7231973 DOI: 10.1016/j.ynstr.2019.100207] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 12/19/2019] [Indexed: 01/27/2023] Open
Abstract
In the 1980s particular endogenous metabolites of progesterone and of deoxycorticosterone were revealed to be potent, efficacious, positive allosteric modulators (PAMs) of the GABAA receptor (GABAAR). These reports were followed by the discovery that such steroids may be synthesised not only in peripheral endocrine glands, but locally in the central nervous system (CNS), to potentially act as paracrine, or autocrine "neurosteroid" messengers, thereby fine tuning neuronal inhibition. These discoveries triggered enthusiasm to elucidate the physiological role of such neurosteroids and explore whether their levels may be perturbed in particular psychiatric and neurological disorders. In preclinical studies the GABAAR-active steroids were shown to exhibit anxiolytic, anticonvulsant, analgesic and sedative properties and at relatively high doses to induce a state of general anaesthesia. Collectively, these findings encouraged efforts to investigate the therapeutic potential of neurosteroids and related synthetic analogues. However, following over 30 years of investigation, realising their possible medical potential has proved challenging. The recent FDA approval for the natural neurosteroid allopregnanolone (brexanolone) to treat postpartum depression (PPD) should trigger renewed enthusiasm for neurosteroid research. Here we focus on the influence of neuroactive steroids on GABA-ergic signalling and on the challenges faced in developing such steroids as anaesthetics, sedatives, analgesics, anticonvulsants, antidepressants and as treatments for neurodegenerative disorders.
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Affiliation(s)
- Delia Belelli
- Systems Medicine, Neuroscience, Mail Box 6, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, United Kingdom
| | - Derk Hogenkamp
- Department of Pharmacology, 110C Med Surge1, Mail Code 4625, University of California, Irvine, School of Medicine, Irvine, CA, 92697, USA
| | - Kelvin W Gee
- Department of Pharmacology, 110C Med Surge1, Mail Code 4625, University of California, Irvine, School of Medicine, Irvine, CA, 92697, USA
| | - Jeremy J Lambert
- Systems Medicine, Neuroscience, Mail Box 6, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, United Kingdom
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26
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Sze Y, Brunton PJ. Sex, stress and steroids. Eur J Neurosci 2019; 52:2487-2515. [DOI: 10.1111/ejn.14615] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 10/01/2019] [Accepted: 10/03/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Ying Sze
- Centre for Discovery Brain Sciences University of Edinburgh Edinburgh UK
| | - Paula J. Brunton
- Centre for Discovery Brain Sciences University of Edinburgh Edinburgh UK
- Zhejiang University‐University of Edinburgh Joint Institute Haining Zhejiang China
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27
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Walther A, Tsao C, Pande R, Kirschbaum C, Field E, Berkman L. Do dehydroepiandrosterone, progesterone, and testosterone influence women's depression and anxiety levels? Evidence from hair-based hormonal measures of 2105 rural Indian women. Psychoneuroendocrinology 2019; 109:104382. [PMID: 31374371 PMCID: PMC6842697 DOI: 10.1016/j.psyneuen.2019.104382] [Citation(s) in RCA: 12] [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: 01/12/2019] [Revised: 06/16/2019] [Accepted: 07/16/2019] [Indexed: 01/19/2023]
Abstract
Depressive and anxiety disorders substantially contribute to the global burden of disease, particularly in poor countries. Higher prevalence rates for both disorders among women indicate sex hormones may be integrated in the pathophysiology of these disorders. The Kshetriya Gramin Financial Services study surveyed a random sample of 4160 households across 876 villages in rural Tamil Nadu, India. An interviewer-administered questionnaire was conducted to quantify depressive (K6-D) and anxiety (K6-A) symptoms. Alongside, hair samples for sex hormone profiling were collected from a subsample of 2105 women aged 18-85 years. Importantly, 5.9%, 14.8%, and 46.3% of samples contained non-detectable hormone levels for dehydroepiandrosterone, progesterone, and testosterone, respectively. Our primary analysis imputes values for the non-detectable sample and we check robustness of results when non-detectable values are dropped. In this cohort of women from rural India, higher depressive symptomatology is associated with lower levels of dehydroepiandrosterone and higher depressive and anxiety symptoms are associated with higher levels of testosterone. Progesterone shows no clear association with either depressive or anxiety symptoms. These results support a potential protective effect of higher endogenous dehydroepiandrosterone levels. An important caveat on the potential negative effect of hair testosterone levels on women's mental health is that the testosterone analysis is sensitive to how non-detectable values are treated.
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Affiliation(s)
- A Walther
- Biological Psychology, TU Dresden, Germany.
| | - C Tsao
- Princeton University, USA
| | - R Pande
- Department of Economics, Yale University, USA
| | | | - E Field
- Economics Department, Duke Trinity College of Arts & Sciences, USA
| | - L Berkman
- Center for Population and Development Studies, Harvard University, USA
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Zorumski CF, Paul SM, Covey DF, Mennerick S. Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond. Neurobiol Stress 2019; 11:100196. [PMID: 31649968 PMCID: PMC6804800 DOI: 10.1016/j.ynstr.2019.100196] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 09/24/2019] [Indexed: 01/22/2023] Open
Abstract
The recent FDA approval of the neurosteroid, brexanolone (allopregnanolone), as a treatment for women with postpartum depression, and successful trials of a related neuroactive steroid, SGE-217, for men and women with major depressive disorder offer the hope of a new era in treating mood and anxiety disorders based on the potential of neurosteroids as modulators of brain function. This review considers potential mechanisms contributing to antidepressant and anxiolytic effects of allopregnanolone and other GABAergic neurosteroids focusing on their actions as positive allosteric modulators of GABAA receptors. We also consider their roles as endogenous "stress" modulators and possible additional mechanisms contributing to their therapeutic effects. We argue that further understanding of the molecular, cellular, network and psychiatric effects of neurosteroids offers the hope of further advances in the treatment of mood and anxiety disorders.
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Affiliation(s)
- Charles F. Zorumski
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
- Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA
- The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Steven M. Paul
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
- The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Douglas F. Covey
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA
- The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Steven Mennerick
- Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
- Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA
- The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA
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Allopregnanolone-based treatments for postpartum depression: Why/how do they work? Neurobiol Stress 2019; 11:100198. [PMID: 31709278 PMCID: PMC6838978 DOI: 10.1016/j.ynstr.2019.100198] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 10/12/2019] [Accepted: 10/16/2019] [Indexed: 01/01/2023] Open
Abstract
Recent FDA approval of an allopregnanolone-based treatment specifically for postpartum depression, brexanolone, now commercially called Zulresso®, is an exciting development for patients and families impacted by postpartum depression and allows us to start asking questions about why and how this compound is so effective. Allopregnanolone is a neuroactive steroid, or neurosteroid, which can be synthesized from steroid hormone precursors, such as progesterone, or synthesized de novo from cholesterol. Neurosteroids are positive allosteric modulators at GABAA receptors (GABAARs), a property which is thought to mediate the therapeutic effects of these compounds. However, the durability of effect of brexanolone in clinical trials questions the mechanism of action mediating the remarkable antidepressant effects, leading us to ask why and how does this drug work. Asking why this drug is effective may provide insight into the underlying neurobiology of postpartum depression. Exploring how this drug works will potentially elucidate a novel antidepressant mechanism of action and may provide useful information for next generation drug development. In this review, we examine the clinical and preclinical evidence supporting a role for allopregnanolone in the underlying neurobiology of postpartum depression as well as foundational evidence supporting the therapeutic effects of allopregnanolone for treatment of postpartum depression.
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A Novel 3-Phytosterone-9α-Hydroxylase Oxygenation Component and Its Application in Bioconversion of 4-Androstene-3,17-Dione to 9α-Hydroxy-4-Androstene-3,17-Dione Coupling with A NADH Regeneration Formate Dehydrogenase. Molecules 2019; 24:molecules24142534. [PMID: 31336696 PMCID: PMC6680482 DOI: 10.3390/molecules24142534] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 07/01/2019] [Accepted: 07/09/2019] [Indexed: 11/17/2022] Open
Abstract
9α-Hydroxy-4-androstene-3,17-dione (9-OH-AD) is one of the significant intermediates for the preparation of β-methasone, dexamethasone, and other steroids. In general, the key enzyme that enables the biotransformation of 4-androstene-3,17-dione (AD) to 9-OH-AD is 3-phytosterone-9α-hydroxylase (KSH), which consists of two components: a terminal oxygenase (KshA) and ferredoxin reductase (KshB). The reaction is carried out with the concomitant oxidation of NADH to NAD+. In this study, the more efficient 3-phytosterone-9α-hydroxylase oxygenase (KshC) from the Mycobacterium sp. strain VKM Ac-1817D was confirmed and compared with reported KshA. To evaluate the function of KshC on the bioconversion of AD to 9-OH-AD, the characterization of KshC and the compounded system of KshB, KshC, and NADH was constructed. The optimum ratio of KSH oxygenase to reductase content was 1.5:1. An NADH regeneration system was designed by introducing a formate dehydrogenase, further confirming that a more economical process for biological transformation from AD to 9-OH-AD was established. A total of 7.78 g of 9-OH-AD per liter was achieved through a fed-batch process with a 92.11% conversion rate (mol/mol). This enzyme-mediated hydroxylation method provides an environmentally friendly and economical strategy for the production of 9-OH-AD.
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31
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Pinna G. Animal Models of PTSD: The Socially Isolated Mouse and the Biomarker Role of Allopregnanolone. Front Behav Neurosci 2019; 13:114. [PMID: 31244621 PMCID: PMC6579844 DOI: 10.3389/fnbeh.2019.00114] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 05/14/2019] [Indexed: 12/18/2022] Open
Abstract
Post-traumatic stress disorder (PTSD) is a debilitating undertreated condition that affects 8%-13% of the general population and 20%-30% of military personnel. Currently, there are no specific medications that reduce PTSD symptoms or biomarkers that facilitate diagnosis, inform treatment selection or allow monitoring drug efficacy. PTSD animal models rely on stress-induced behavioral deficits that only partially reproduce PTSD neurobiology. PTSD heterogeneity, including comorbidity and symptoms overlap with other mental disorders, makes this attempt even more complicated. Allopregnanolone, a neurosteroid that positively, potently and allosterically modulates GABAA receptors and, by this mechanism, regulates emotional behaviors, is mainly synthesized in brain corticolimbic glutamatergic neurons. In PTSD patients, allopregnanolone down-regulation correlates with increased PTSD re-experiencing and comorbid depressive symptoms, CAPS-IV scores and Simms dysphoria cluster scores. In PTSD rodent models, including the socially isolated mouse, decrease in corticolimbic allopregnanolone biosynthesis is associated with enhanced contextual fear memory and impaired fear extinction. Allopregnanolone, its analogs or agents that stimulate its synthesis offer treatment approaches for facilitating fear extinction and, in general, for neuropsychopathologies characterized by a neurosteroid biosynthesis downregulation. The socially isolated mouse model reproduces several other deficits previously observed in PTSD patients, including altered GABAA receptor subunit subtypes and lack of benzodiazepines pharmacological efficacy. Transdiagnostic behavioral features, including expression of anxiety-like behavior, increased aggression, a behavioral component to reproduce behavioral traits of suicidal behavior in humans, as well as alcohol consumption are heightened in socially isolated rodents. Potentials for assessing novel biomarkers to predict, diagnose, and treat PTSD more efficiently are discussed in view of developing a precision medicine for improved PTSD pharmacological treatments.
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Affiliation(s)
- Graziano Pinna
- The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
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Chronic Antipsychotic Treatment Modulates Aromatase (CYP19A1) Expression in the Male Rat Brain. J Mol Neurosci 2019; 68:311-317. [PMID: 30968339 PMCID: PMC6511348 DOI: 10.1007/s12031-019-01307-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 03/20/2019] [Indexed: 01/20/2023]
Abstract
Antipsychotic drugs, known as the antagonists of dopaminergic receptors, may also affect a large spectrum of other molecular signaling pathways in the brain. Despite the numerous ongoing studies on neurosteroid action and regulation, there are no reports regarding the influence of extended treatment with typical and atypical neuroleptics on brain aromatase (CYP19A1) expression. In the present study, we assessed for the first time aromatase mRNA and protein levels in the brain of rats chronically (28 days) treated with olanzapine, clozapine, and haloperidol using quantitative real-time PCR, end-point RT-PCR, and Western blotting. Both clozapine and haloperidol, but not olanzapine treatment, led to an increase of aromatase mRNA expression in the rat brain. On the other hand, aromatase protein level remained unchanged after drug administration. These results cast a new light on the pharmacology of examined antipsychotics and contribute to a better understanding of the mechanisms responsible for their action. The present report also underlines the complex nature of potential interactions between neuroleptic pharmacological effects and physiology of brain neurosteroid pathways.
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Maguire J. Neuroactive Steroids and GABAergic Involvement in the Neuroendocrine Dysfunction Associated With Major Depressive Disorder and Postpartum Depression. Front Cell Neurosci 2019; 13:83. [PMID: 30906252 PMCID: PMC6418819 DOI: 10.3389/fncel.2019.00083] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 02/19/2019] [Indexed: 12/21/2022] Open
Abstract
Stress and previous adverse life events are well-established risk factors for depression. Further, neuroendocrine disruptions are associated with both major depressive disorder (MDD) and postpartum depression (PPD). However, the mechanisms whereby stress contributes to the underlying neurobiology of depression remains poorly understood. The hypothalamic-pituitary-adrenal (HPA) axis, which mediates the body's neuroendocrine response to stress, is tightly controlled by GABAergic signaling and there is accumulating evidence that GABAergic dysfunction contributes to the impact of stress on depression. GABAergic signaling plays a critical role in the neurobiological effects of stress, not only by tightly controlling the activity of the HPA axis, but also mediating stress effects in stress-related brain regions. Deficits in neuroactive steroids and neurosteroids, some of which are positive allosteric modulators of GABAA receptors (GABAARs), such as allopregnanolone and THDOC, have also been implicated in MDD and PPD, further supporting a role for GABAergic signaling in depression. Alterations in neurosteroid levels and GABAergic signaling are implicated as potential contributing factors to neuroendocrine dysfunction and vulnerability to MDD and PPD. Further, potential novel treatment strategies targeting these proposed underlying neurobiological mechanisms are discussed. The evidence summarized in the current review supports the notion that MDD and PPD are stress-related psychiatric disorders involving neurosteroids and GABAergic dysfunction.
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Affiliation(s)
- Jamie Maguire
- Neuroscience Department, Tufts University School of Medicine, Boston, MA, United States
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34
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Payne JL, Maguire J. Pathophysiological mechanisms implicated in postpartum depression. Front Neuroendocrinol 2019; 52:165-180. [PMID: 30552910 PMCID: PMC6370514 DOI: 10.1016/j.yfrne.2018.12.001] [Citation(s) in RCA: 222] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 11/13/2018] [Accepted: 12/11/2018] [Indexed: 02/06/2023]
Abstract
This review aims to summarize the diverse proposed pathophysiological mechanisms contributing to postpartum depression, highlighting both clinical and basic science research findings. The risk factors for developing postpartum depression are discussed, which may provide insight into potential neurobiological underpinnings. The evidence supporting a role for neuroendocrine changes, neuroinflammation, neurotransmitter alterations, circuit dysfunction, and the involvement of genetics and epigenetics in the pathophysiology of postpartum depression are discussed. This review integrates clinical and preclinical findings and highlights the diversity in the patient population, in which numerous pathophysiological changes may contribute to this disorder. Finally, we attempt to integrate these findings to understand how diverse neurobiological changes may contribute to a common pathological phenotype. This review is meant to serve as a comprehensive resource reviewing the proposed pathophysiological mechanisms underlying postpartum depression.
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Affiliation(s)
- Jennifer L Payne
- Department of Psychiatry, Women's Mood Disorders Center, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Jamie Maguire
- Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA.
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Abstract
INTRODUCTION Depression and posttraumatic stress disorder (PTSD) are two complex and debilitating psychiatric disorders that result in poor life and destructive behaviors against self and others. Currently, diagnosis is based on subjective rather than objective determinations leading to misdiagnose and ineffective treatments. Advances in novel neurobiological methods have allowed assessment of promising biomarkers to diagnose depression and PTSD, which offers a new means of appropriately treating patients. Areas covered: Biomarkers discovery in blood represents a fundamental tool to predict, diagnose, and monitor treatment efficacy in depression and PTSD. The potential role of altered HPA axis, epigenetics, NPY, BDNF, neurosteroid biosynthesis, the endocannabinoid system, and their function as biomarkers for mood disorders is discussed. Insofar, we propose the identification of a biomarker axis to univocally identify and discriminate disorders with large comorbidity and symptoms overlap, so as to provide a base of support for development of targeted treatments. We also weigh in on the feasibility of a future blood test for early diagnosis. Expert commentary: Potential biomarkers have already been assessed in patients' blood and need to be further validated through multisite large clinical trial stratification. Another challenge is to assess the relation among several interdependent biomarkers to form an axis that identifies a specific disorder and secures the best-individualized treatment. The future of blood-based tests for PTSD and depression is not only on the horizon but, possibly, already around the corner.
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Affiliation(s)
- Dario Aspesi
- a The Psychiatric Institute, Department of Psychiatry , University of Illinois at Chicago , Chicago , IL , USA
| | - Graziano Pinna
- a The Psychiatric Institute, Department of Psychiatry , University of Illinois at Chicago , Chicago , IL , USA
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Abstract
OBJECTIVES Anxiety and adjustment disorders are among the most prevalent mental health conditions. This review focuses on γ-aminobutyric acid receptor type A (GABAAR)-mediated anxiolysis, describing the action of both endogenous and exogenous modulators of GABAAR. Future directions and innovative strategies to alleviate anxiety symptoms are discussed, with a particular emphasis on etifoxine. METHODS We used available data from the recent literature to update the mode of action of anxiolytics. We focussed our search on anxiolytics acting at GABAARs, as well as on the pharmacological properties of formerly and currently prescribed anxiolytics. RESULTS Considering the adverse effects of current treatments aimed at increasing inhibitory controls, optimisation of existing pharmacotherapies is of crucial importance. Among the alternative compounds targeting the GABAergic system, translocator protein (TSPO) ligands, such as etifoxine (EFX), which promote endogenous neurosteroidogenesis, are emerging as promising candidates for anxiety relief. In several papers comparing the efficacy of benzodiazepines and EFX, EFX showed interesting properties with limited side effects. Indeed, neurosteroids are potent GABAAR modulators with highly underrated anxiolytic properties. CONCLUSIONS Novel therapeutic strategies have been emerging following the recognition of neurosteroids as potent anxiolytics. Featured at the top of the list for well-tolerated anxiety relief, TSPO ligands such as etifoxine appear promising.
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Affiliation(s)
- Pierrick Poisbeau
- a Centre National de la Recherche Scientifique and University of Strasbourg, Institute for Cellular and Integrative Neuroscience (INCI) , Strasbourg , France
| | - Geraldine Gazzo
- a Centre National de la Recherche Scientifique and University of Strasbourg, Institute for Cellular and Integrative Neuroscience (INCI) , Strasbourg , France
| | - Laurent Calvel
- a Centre National de la Recherche Scientifique and University of Strasbourg, Institute for Cellular and Integrative Neuroscience (INCI) , Strasbourg , France
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Mifflin K, Baker GB, Kerr BJ. Effect of voluntary wheel running on neuroactive steroid levels in murine experimental autoimmune encephalomyelitis. Neurosci Lett 2018; 685:150-154. [PMID: 30171909 DOI: 10.1016/j.neulet.2018.08.040] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 08/21/2018] [Accepted: 08/27/2018] [Indexed: 12/18/2022]
Abstract
Increasing evidence from both clinical and animal research has implicated changes in neuroactive steroids (rapid acting steroids that act as allosteric modulators at NMDA and/or GABA-A receptors) in multiple sclerosis. These changes have been linked to clinical differences in disease severity, prevention of disease development, as well as the disease state (relapsing vs progressive) in patients with multiple sclerosis. Previous research has also linked changes in neuroactive steroid levels to the beneficial effects of exercise in certain disorders such as traumatic brain injury and post-traumatic stress disorder. The present study therefore examined whether voluntary wheel running could modulate any of the reported changes in neuroactive steroids associated with the EAE model of multiple sclerosis. Female mice with EAE who ran were found to have significantly increased levels of brain pregnenolone compared to male EAE mice who ran. In contrast, male mice with EAE were found to have significantly higher levels of brain allopregnanolone compared to female mice with EAE regardless of exercise. Overall, these results indicate that exercise has moderate beneficial effects on brain neuroactive steroid levels in EAE. These changes may be related to other beneficial responses to exercise, such as improvements in disease severity, in EAE and/or multiple sclerosis.
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Affiliation(s)
- Katherine Mifflin
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2E1, Canada.
| | - Glen B Baker
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2E1, Canada; Department of Psychiatry (NRU), University of Alberta, Edmonton, AB, T6G 2B7, Canada
| | - Bradley J Kerr
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2E1, Canada; Department of Pharmacology, University of Alberta, Edmonton, AB, T6E 2H7, Canada; Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, AB, T6G 2G3, Canada
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Qi X, Luchetti S, Verwer RWH, Sluiter AA, Mason MRJ, Zhou J, Swaab DF. Alterations in the steroid biosynthetic pathways in the human prefrontal cortex in mood disorders: A post-mortem study. Brain Pathol 2018; 28:536-547. [PMID: 28752602 PMCID: PMC8028289 DOI: 10.1111/bpa.12548] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 07/20/2017] [Indexed: 01/08/2023] Open
Abstract
Altered levels of steroids have been reported in the brain, cerebral spinal fluid and plasma of patients with mood disorders. Neuroimaging studies have reported both functional and structural alterations in mood disorders, for instance in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC). In order to determine whether the endogenous production of steroids is altered in the ACC and DLPFC of patients with major depressive disorder (MDD) or bipolar disorder (BPD), quantitative real-time PCR was performed to detect mRNA expression level of key enzymes in the steroid biosynthetic pathways. In MDD, a significant decrease in mRNA level of cytochrome P450 17A1 (CYP17A1, synthesizing C19 ketosteroids) in the ACC and a significant increase in mRNA levels of hydroxysteroid sulfotransferase 2A1 [SULT2A1, catalyzing the sulfate conjugation of dehydroepiandrosterone (DHEA)] were observed in the DLPFC, suggesting alterations in DHEA and its sulfate metabolite DHEAS levels. Decreased intensity and distribution of CYP17A1 immunohistochemical staining was found in the ACC of MDD patients. Interestingly, there was a significant positive correlation between the mRNA levels of CYP17A1 and tyrosine-related kinase B (TrkB) full length isoform. In a unique post-mortem human brain slice culture paradigm, BDNF mRNA expression was found to be significantly increased following incubation with DHEA. Together, these data indicate a close relationship between DHEA and BDNF-TrkB pathways in depression. Furthermore, in the DLPFC, higher mRNA levels of 11β-hydroxysteroid dehydrogenase-1 (HSD11B1, reducing cortisone to the active hormone cortisol) and steroidogenic acute regulatory protein (STAR, facilitating the shuttle of cholesterol through the intermembrane space) were found in the MDD patients and BPD patients, respectively. In conclusion, this study suggests the presence of a disturbance in the endogenous synthesis of DHEA and DHEAS in mood disorders, which has a close relationship with BDNF-TrkB signaling.
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Affiliation(s)
- Xin‐Rui Qi
- Netherlands Institute for NeuroscienceAn Institute of the Royal Netherlands Academy of Arts and SciencesAmsterdamthe Netherlands
- CAS Key Laboratory of Brain Function and Diseases, School of Life SciencesUniversity of Science and Technology of ChinaHefeiAnhuiP. R. China
| | - Sabina Luchetti
- Netherlands Institute for NeuroscienceAn Institute of the Royal Netherlands Academy of Arts and SciencesAmsterdamthe Netherlands
| | - Ronald W. H. Verwer
- Netherlands Institute for NeuroscienceAn Institute of the Royal Netherlands Academy of Arts and SciencesAmsterdamthe Netherlands
| | - Arja A. Sluiter
- Netherlands Institute for NeuroscienceAn Institute of the Royal Netherlands Academy of Arts and SciencesAmsterdamthe Netherlands
| | - Matthew R. J. Mason
- Netherlands Institute for NeuroscienceAn Institute of the Royal Netherlands Academy of Arts and SciencesAmsterdamthe Netherlands
| | - Jiang‐Ning Zhou
- CAS Key Laboratory of Brain Function and Diseases, School of Life SciencesUniversity of Science and Technology of ChinaHefeiAnhuiP. R. China
| | - Dick F. Swaab
- Netherlands Institute for NeuroscienceAn Institute of the Royal Netherlands Academy of Arts and SciencesAmsterdamthe Netherlands
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Ivanova GP, Gorobets LN, Litvinov AV, Bulanov VS, Vasilenko LM. [A role of progesterone and its metabolites in regulation functions of the brain]. Zh Nevrol Psikhiatr Im S S Korsakova 2018; 118:129-137. [PMID: 29927417 DOI: 10.17116/jnevro201811851129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The review presents literature data reflecting the nature and mechanism of the effect of progesterone and its metabolites on human and animal brain structures. Particular attention is paid to neuroprotective, anticonvulsant, anti-anxiety and sedative properties of this hormone, which determines the prospect of its use for the prevention and treatment of human neurodegenerative diseases, epilepsy, sleep disorders, and anxiety-depressive spectrum disorders, including premenstrual and climacteric syndromes.
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Affiliation(s)
- G P Ivanova
- Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow, Russia
| | - L N Gorobets
- Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow, Russia
| | - A V Litvinov
- Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow, Russia
| | - V S Bulanov
- Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow, Russia
| | - L M Vasilenko
- Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow, Russia
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40
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De Nicola AF, Garay LI, Meyer M, Guennoun R, Sitruk-Ware R, Schumacher M, Gonzalez Deniselle MC. Neurosteroidogenesis and progesterone anti-inflammatory/neuroprotective effects. J Neuroendocrinol 2018; 30. [PMID: 28675779 DOI: 10.1111/jne.12502] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 06/29/2017] [Accepted: 06/30/2017] [Indexed: 12/19/2022]
Abstract
Progesterone shows anti-inflammatory and promyelinating effects in mice with experimental autoimmune encephalomyelitis (EAE), a commonly used model for multiple sclerosis (MS). Because neurosteroids have been implicated as protective factors for MS and EAE, we analysed the expression of neurosteroidogenic enzymes in the compromised spinal cord of EAE mice. EAE was induced in female C57Bl6 mice, which were then killed on day 16 after induction. Progesterone was given by pellet implantation 1 week before EAE induction. Untreated EAE mice showed decreased mRNAs for the steroidogenic acute regulatory protein (Star), voltage-dependent anion channel (VDAC), cholesterol side-chain cleavage (P450scc), 5α-reductase, 3α-hydroxysteroid dehydrogenase (3α-HSOR) and aromatase, whereas changes of 3β-hydroxysteroid dehydrogenase (3β-HSD) were not significant. mRNA translocator protein (18 kDa) (TSPO) was elevated, concomitantly with a reactive microgliosis. EAE mice also showed abnormal mitochondrial ultrastructure in axons and neuronal bodies, as well as reduced expression of fission and fusion protein mRNAs. Progesterone pretreatment before EAE induction increased Star, VDAC, P450scc, 5α-reductase type I, 3α-HSOR and aromatase mRNAs and did not modify 3β-HSD. TSPO mRNA was decreased, possibly as a result of reversal of microgliosis. Progesterone pretreatment also improved mitochondrial ultrastructure and increased fission/fusion protein mRNAs. These mitochondrial effects may be part of the progesterone recovery of neurosteroidogenesis. The enzymes 3β-HSD, 3α-HSOR and 5α-reductase are also responsible for the formation of androgens. Because MS patients and EAE rodents show changes of central androgen levels, it is likely that, together with progestins and oestrogens, neuroandrogens afford neuroprotection for EAE and MS. The data reviewed suggest that enhanced synthesis of neurosteroids contributes in an auto/paracrine manner to reinforce the neuroprotective and anti-inflammatory effects of exogenous progesterone given to EAE mice.
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Affiliation(s)
- A F De Nicola
- Department of Human Biochemistry, Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
- Instituto de Biologia y Medicina Experimental-CONICET, Buenos Aires, Argentina
| | - L I Garay
- Department of Human Biochemistry, Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
- Instituto de Biologia y Medicina Experimental-CONICET, Buenos Aires, Argentina
| | - M Meyer
- Instituto de Biologia y Medicina Experimental-CONICET, Buenos Aires, Argentina
| | - R Guennoun
- U1195 Inserm and Université Paris-Sud, Le Kremlin-Bicêtre, France
| | | | - M Schumacher
- U1195 Inserm and Université Paris-Sud, Le Kremlin-Bicêtre, France
| | - M C Gonzalez Deniselle
- The Population Council, New York, NY, USA
- Department of Physiology and Biophysics, Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
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Belelli D, Brown AR, Mitchell SJ, Gunn BG, Herd MB, Phillips GD, Seifi M, Swinny JD, Lambert JJ. Endogenous neurosteroids influence synaptic GABA A receptors during postnatal development. J Neuroendocrinol 2018; 30. [PMID: 28905487 DOI: 10.1111/jne.12537] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2017] [Revised: 08/22/2017] [Accepted: 09/10/2017] [Indexed: 12/12/2022]
Abstract
GABA plays a key role in both embryonic and neonatal brain development. For example, during early neonatal nervous system maturation, synaptic transmission, mediated by GABAA receptors (GABAA Rs), undergoes a temporally specific form of synaptic plasticity to accommodate the changing requirements of maturing neural networks. Specifically, the duration of miniature inhibitory postsynaptic currents (mIPSCs), resulting from vesicular GABA activating synaptic GABAA Rs, is reduced, permitting neurones to appropriately influence the window for postsynaptic excitation. Conventionally, programmed expression changes to the subtype of synaptic GABAA R are primarily implicated in this plasticity. However, it is now evident that, in developing thalamic and cortical principal- and inter-neurones, an endogenous neurosteroid tone (eg, allopregnanolone) enhances synaptic GABAA R function. Furthermore, a cessation of steroidogenesis, as a result of a lack of substrate, or a co-factor, appears to be primarily responsible for early neonatal changes to GABAergic synaptic transmission, followed by further refinement, which results from subsequent alterations of the GABAA R subtype. The timing of this cessation of neurosteroid influence is neurone-specific, occurring by postnatal day (P)10 in the thalamus but approximately 1 week later in the cortex. Neurosteroid levels are not static and change dynamically in a variety of physiological and pathophysiological scenarios. Given that GABA plays an important role in brain development, abnormal perturbations of neonatal GABAA R-active neurosteroids may have not only a considerable immediate, but also a longer-term impact upon neural network activity. Here, we review recent evidence indicating that changes in neurosteroidogenesis substantially influence neonatal GABAergic synaptic transmission. We discuss the physiological relevance of these findings and how the interference of neurosteroid-GABAA R interaction early in life may contribute to psychiatric conditions later in life.
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Affiliation(s)
- D Belelli
- Division of Neuroscience, School of Medicine, Ninewells Hospital, University of Dundee, Dundee, UK
| | - A R Brown
- Division of Neuroscience, School of Medicine, Ninewells Hospital, University of Dundee, Dundee, UK
| | - S J Mitchell
- Division of Neuroscience, School of Medicine, Ninewells Hospital, University of Dundee, Dundee, UK
| | - B G Gunn
- Division of Neuroscience, School of Medicine, Ninewells Hospital, University of Dundee, Dundee, UK
| | - M B Herd
- Division of Neuroscience, School of Medicine, Ninewells Hospital, University of Dundee, Dundee, UK
| | - G D Phillips
- Division of Neuroscience, School of Medicine, Ninewells Hospital, University of Dundee, Dundee, UK
| | - M Seifi
- Institute for Biomedical & Biomolecular Sciences, School of Pharmacy & Biomedical Sciences, University of Portsmouth, Portsmouth, UK
| | - J D Swinny
- Institute for Biomedical & Biomolecular Sciences, School of Pharmacy & Biomedical Sciences, University of Portsmouth, Portsmouth, UK
| | - J J Lambert
- Division of Neuroscience, School of Medicine, Ninewells Hospital, University of Dundee, Dundee, UK
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Giatti S, Mastrangelo R, D'Antonio M, Pesaresi M, Romano S, Diviccaro S, Caruso D, Mitro N, Melcangi RC. Neuroactive steroids and diabetic complications in the nervous system. Front Neuroendocrinol 2018; 48:58-69. [PMID: 28739507 DOI: 10.1016/j.yfrne.2017.07.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 07/19/2017] [Accepted: 07/20/2017] [Indexed: 12/21/2022]
Abstract
Important complications of diabetes mellitus in the nervous system are represented by diabetic peripheral neuropathy and diabetic encephalopathy. In this context, an important link is represented by neuroactive steroids (i.e., steroids coming from peripheral glands and affecting nervous functionality as well as directly synthesized in the nervous system). Indeed, diabetes does not only affect the reproductive axis and consequently the levels of sex steroid hormones, but also those of neuroactive steroids. Indeed, as will be here summarized, the levels of these neuromodulators present in the central and peripheral nervous system are affected by the pathology in a sex-dimorphic way. In addition, some of these neuroactive steroids, such as the metabolites of progesterone or testosterone, as well as pharmacological tools able to increase their levels have been demonstrated, in experimental models, to be promising protective agents against diabetic peripheral neuropathy and diabetic encephalopathy.
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Affiliation(s)
- S Giatti
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - R Mastrangelo
- Division of Genetic and Cell Biology, San Raffaele Scientific Institute, DIBIT, Milano, Italy
| | - M D'Antonio
- Division of Genetic and Cell Biology, San Raffaele Scientific Institute, DIBIT, Milano, Italy
| | - M Pesaresi
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - S Romano
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - S Diviccaro
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - D Caruso
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - N Mitro
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - R C Melcangi
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
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Mačiukaitė L, Jarutytė L, Rukšėnas O. The Effects of Menstrual Cycle Phase on Processing of Emotional Images. J PSYCHOPHYSIOL 2017. [DOI: 10.1027/0269-8803/a000179] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Abstract. The ovarian hormone levels can affect subjective ratings and modulate late positive potential (LPP) amplitudes evoked by images of varying appeal. The present study examines how different progesterone levels influence the valence, arousal ratings and mean LPP amplitudes evoked by pleasant, neutral, and unpleasant images. Twenty-three healthy females were grouped by menstrual cycle days (estradiol and progesterone levels): 10 were included in the follicular phase group and 13 were included in the luteal phase group. Each female rated the affective images in terms of valence and arousal while event-related potentials (ERPs) were measured. The valence ratings of pleasant images were higher in follicular phase group than in luteal, but the same effect was not seen in the arousal ratings. The arousal ratings to unpleasant images were higher than those to pleasant in luteal, but not in follicular phase group. However, the mean amplitude of the early LPP (450–700 ms) was significantly greater to pleasant than to neutral and unpleasant stimuli, but did not differ between follicular and luteal phase groups. The mean amplitude of the late LPP (700–950 ms) was significantly larger to pleasant and unpleasant compared to neutral images, but did not differ between menstrual cycle phase groups. Correlation analysis showed a significant negative relationship between progesterone levels and arousal ratings of pleasant and unpleasant images in luteal phase group. Arousal scores for unpleasant images negatively correlated with mean LPP amplitudes to unpleasant images at Pz site in the luteal phase group. The present study provides evidence that subjective ratings of affective images of different attractiveness could be influenced by female menstrual cycle phase, but mean amplitudes of LPP (450–950 ms) are not affected. However, results of correlational analysis suggest that valence, arousal ratings and mean LPP amplitudes are susceptible to the influence of hormone progesterone in luteal phase.
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Affiliation(s)
- Laura Mačiukaitė
- Department of Neurobiology and Biophysics, Vilnius University, Lithuania
| | - Lina Jarutytė
- Department of Neurobiology and Biophysics, Vilnius University, Lithuania
| | - Osvaldas Rukšėnas
- Department of Neurobiology and Biophysics, Vilnius University, Lithuania
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Huang YC, Hung CF, Lin PY, Lee Y, Wu CC, Hsu ST, Chen CC, Chong MY, Lin CH, Wang LJ. Gender differences in susceptibility to schizophrenia: Potential implication of neurosteroids. Psychoneuroendocrinology 2017; 84:87-93. [PMID: 28686904 DOI: 10.1016/j.psyneuen.2017.06.017] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 06/21/2017] [Accepted: 06/23/2017] [Indexed: 11/28/2022]
Abstract
Past research has indicated gender differences in the clinical characteristics and course of schizophrenia. In this study, we investigated whether gender differences in the manifestation of schizophrenia are correlated with neurosteroids, including dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and pregnenolone. We further explored the potential relationship between the aforementioned neurosteroids and psychopathology. We recruited 65 schizophrenic patients (36 males and 29 females) and 103 healthy control subjects (47 males and 56 females) and obtained blood samples from the subjects in the morning while in a fasting state to determine the serum levels of DHEA, DHEA-S, and pregnenolone. The psychopathology and mood symptoms of patients with schizophrenia were evaluated using the Positive and Negative Syndrome Scale (PANSS) and 17-item Hamilton Depression Rating Scale, respectively. Compared to the male control subjects, male patients with schizophrenia had significantly lower serum levels of DHEA and pregnenolone. In males with schizophrenia, the serum levels of DHEA and DHEA-S were associated with the age of onset and the duration of illness, while pregnenolone levels were associated with general symptoms of the PANSS. However, none of the neurosteroid levels were different between the female patients with schizophrenia and the female controls, and no significant correlation between neurosteroid levels and psychopathology evaluations was found among the schizophrenic females. Neurosteroids, including DHEA, DHEA-S, and pregnenolone, are involved in the pathophysiology of schizophrenia in male patients, but not in female ones. Therefore, our findings suggest that neurosteroids may be associated with gender differences in susceptibility to schizophrenia.
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Affiliation(s)
- Yu-Chi Huang
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Chung Shan Medical University School of Medicine, Taichung, Taiwan
| | - Chi-Fa Hung
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Pao-Yen Lin
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Yu Lee
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chih-Ching Wu
- Molecular Medicine Research Center, Chang Gung University, Tao-Yuan, Taiwan; Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Tao-Yuan, Taiwan
| | - Su-Ting Hsu
- Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan
| | - Chien-Chih Chen
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Mian-Yoon Chong
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chieh-Hsin Lin
- Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Liang-Jen Wang
- Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
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Locci A, Pinna G. Neurosteroid biosynthesis down-regulation and changes in GABA A receptor subunit composition: a biomarker axis in stress-induced cognitive and emotional impairment. Br J Pharmacol 2017; 174:3226-3241. [PMID: 28456011 DOI: 10.1111/bph.13843] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 04/05/2017] [Accepted: 04/12/2017] [Indexed: 12/26/2022] Open
Abstract
By rapidly modulating neuronal excitability, neurosteroids regulate physiological processes, such as responses to stress and development. Excessive stress affects their biosynthesis and causes an imbalance in cognition and emotions. The progesterone derivative, allopregnanolone (Allo) enhances extrasynaptic and postsynaptic inhibition by directly binding at GABAA receptors, and thus, positively and allosterically modulates the function of GABA. Allo levels are decreased in stress-induced psychiatric disorders, including depression and post-traumatic stress disorder (PTSD), and elevating Allo levels may be a valid therapeutic approach to counteract behavioural dysfunction. While benzodiazepines are inefficient, selective serotonin reuptake inhibitors (SSRIs) represent the first choice treatment for depression and PTSD. Their mechanisms to improve behaviour in preclinical studies include neurosteroidogenic effects at low non-serotonergic doses. Unfortunately, half of PTSD and depressed patients are resistant to current prescribed 'high' dosage of these drugs that engage serotonergic mechanisms. Unveiling novel biomarkers to develop more efficient treatment strategies is in high demand. Stress-induced down-regulation of neurosteroid biosynthesis and changes in GABAA receptor subunit expression offer a putative biomarker axis to develop new PTSD treatments. The advantage of stimulating Allo biosynthesis relies on the variety of neurosteroidogenic receptors to be targeted, including TSPO and endocannabinoid receptors. Furthermore, stress favours a GABAA receptor subunit composition with higher sensitivity for Allo. The use of synthetic analogues of Allo is a valuable alternative. Pregnenolone or drugs that stimulate its levels increase Allo but also sulphated steroids, including pregnanolone sulphate which, by inhibiting NMDA tonic neurotransmission, provides neuroprotection and cognitive benefits. In this review, we describe current knowledge on the effects of stress on neurosteroid biosynthesis and GABAA receptor neurotransmission and summarize available pharmacological strategies that by enhancing neurosteroidogenesis are relevant for the treatment of SSRI-resistant patients. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc.
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Affiliation(s)
- Andrea Locci
- The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Graziano Pinna
- The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
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Rasmusson AM, Marx CE, Pineles SL, Locci A, Scioli-Salter ER, Nillni YI, Liang JJ, Pinna G. Neuroactive steroids and PTSD treatment. Neurosci Lett 2017; 649:156-163. [PMID: 28215878 DOI: 10.1016/j.neulet.2017.01.054] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Revised: 01/22/2017] [Accepted: 01/23/2017] [Indexed: 01/08/2023]
Abstract
This review highlights early efforts to translate pre-clinical and clinical findings regarding the role of neuroactive steroids in stress adaptation and PTSD into new therapeutics for PTSD. Numerous studies have demonstrated PTSD-related alterations in resting levels or the reactivity of neuroactive steroids and their targets. These studies also have demonstrated substantial variability in the dysfunction of specific neuroactive steroid systems among PTSD subpopulations. These variabilities have been related to the developmental timing of trauma, severity and type of trauma, genetic background, sex, reproductive state, lifestyle influences such as substance use and exercise, and the presence of comorbid conditions such as depression and chronic pain. Nevertheless, large naturalistic studies and a small placebo-controlled interventional study have revealed generally positive effects of glucocorticoid administration in preventing PTSD after trauma, possibly mediated by glucocorticoid receptor-mediated effects on other targets that impact PTSD risk, including other neuroactive steroid systems. In addition, clinical and preclinical studies show that administration of glucocorticoids, 17β-estradiol, and GABAergic neuroactive steroids or agents that enhance their synthesis can facilitate extinction and extinction retention, depending on dose and timing of dose in relation to these complex PTSD-relevant recovery processes. This suggests that clinical trials designed to test neuroactive steroid therapeutics in PTSD may benefit from such considerations; typical continuous dosing regimens may not be optimal. In addition, validated and clinically accessible methods for identifying specific neuroactive steroid system abnormalities at the individual level are needed to optimize both clinical trial design and precision medicine based treatment targeting.
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Affiliation(s)
- Ann M Rasmusson
- National Center for PTSD, Women's Health Science Division, Department of Veterans Affairs 150 South Huntington Avenue, Boston, MA 02135, USA; VA Boston Healthcare System 150 South Huntington Avenue, Boston, MA 02135, USA; Boston University School of Medicine 72 E Concord St, Boston, MA 02118, USA.
| | - Christine E Marx
- Durham VA Medical Center, VA Mid-Atlantic MIRECC,and Duke University Medical Center, 508 Fulton Street, Durham, NC 27705, USA
| | - Suzanne L Pineles
- National Center for PTSD, Women's Health Science Division, Department of Veterans Affairs 150 South Huntington Avenue, Boston, MA 02135, USA; Boston University School of Medicine 72 E Concord St, Boston, MA 02118, USA
| | - Andrea Locci
- The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 W. Taylor Str., Chicago, IL 60612, USA
| | - Erica R Scioli-Salter
- VA Boston Healthcare System 150 South Huntington Avenue, Boston, MA 02135, USA; Boston University School of Medicine 72 E Concord St, Boston, MA 02118, USA
| | - Yael I Nillni
- National Center for PTSD, Women's Health Science Division, Department of Veterans Affairs 150 South Huntington Avenue, Boston, MA 02135, USA; Boston University School of Medicine 72 E Concord St, Boston, MA 02118, USA
| | - Jennifer J Liang
- Boston University School of Medicine 72 E Concord St, Boston, MA 02118, USA
| | - Graziano Pinna
- The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 W. Taylor Str., Chicago, IL 60612, USA
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Kosek E, Martinsen S, Gerdle B, Mannerkorpi K, Löfgren M, Bileviciute-Ljungar I, Fransson P, Schalling M, Ingvar M, Ernberg M, Jensen KB. The translocator protein gene is associated with symptom severity and cerebral pain processing in fibromyalgia. Brain Behav Immun 2016; 58:218-227. [PMID: 27448744 DOI: 10.1016/j.bbi.2016.07.150] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Revised: 06/17/2016] [Accepted: 07/19/2016] [Indexed: 12/12/2022] Open
Abstract
The translocator protein (TSPO) is upregulated during glia activation in chronic pain patients. TSPO constitutes the rate-limiting step in neurosteroid synthesis, thus modulating synaptic transmission. Related serotonergic mechanisms influence if pro- or anti-nociceptive neurosteroids are produced. This study investigated the effects of a functional genetic polymorphism regulating the binding affinity to the TSPO, thus affecting symptom severity and cerebral pain processing in fibromyalgia patients. Gene-to-gene interactions with a functional polymorphism of the serotonin transporter gene were assessed. Fibromyalgia patients (n=126) were genotyped regarding the polymorphisms of the TSPO (rs6971) and the serotonin transporter (5-HTTLPR/rs25531). Functional magnetic resonance imaging (n=24) was used to study brain activation during individually calibrated pressure pain. Compared to mixed/low TSPO affinity binders, the high TSPO affinity binders rated more severe pain (p=0.016) and fibromyalgia symptoms (p=0.02). A significant interaction was found between the TSPO and the serotonin transporter polymorphisms regarding pain severity (p<0.0001). Functional connectivity analyses revealed that the TSPO high affinity binding group had more pronounced pain-evoked functional connectivity in the right frontoparietal network, between the dorsolateral prefrontal area and the parietal cortex. In conclusion, fibromyalgia patients with the TSPO high affinity binding genotype reported a higher pain intensity and more severe fibromyalgia symptoms compared to mixed/low affinity binders, and this was modulated by interaction with the serotonin transporter gene. To our knowledge this is the first evidence of functional genetic polymorphisms affecting pain severity in FM and our findings are in line with proposed glia-related mechanisms. Furthermore, the functional magnetic resonance findings indicated an effect of translocator protein on the affective-motivational components of pain perception.
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Affiliation(s)
- Eva Kosek
- Department of Clinical Neuroscience and Osher Center, Karolinska Insitutet, Department of Neuroradiology, Karolinska University Hospital, SE-171 77 Stockholm, Sweden; Stockholm Spine Center, Löwenströmska Hospital, 198 84 Upplands Väsby, Sweden.
| | - Sofia Martinsen
- Department of Clinical Neuroscience and Osher Center, Karolinska Insitutet, Department of Neuroradiology, Karolinska University Hospital, SE-171 77 Stockholm, Sweden.
| | - Björn Gerdle
- Pain and Rehabilitation Centre, and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
| | - Kaisa Mannerkorpi
- Department of Health and Rehabilitation/Physiotherapy, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden; University of Gothenburg Centre for Person-centred Care (GPCC), Sahlgrenska Academy, Gothenburg, Sweden.
| | - Monika Löfgren
- Department of Clinical Sciences, Karolinska Institutet and Department of Rehabilitation Medicine, Danderyd Hospital, SE-182 88 Stockholm, Sweden.
| | - Indre Bileviciute-Ljungar
- Department of Clinical Sciences, Karolinska Institutet and Department of Rehabilitation Medicine, Danderyd Hospital, SE-182 88 Stockholm, Sweden.
| | - Peter Fransson
- Department of Clinical Neuroscience and Osher Center, Karolinska Insitutet, Department of Neuroradiology, Karolinska University Hospital, SE-171 77 Stockholm, Sweden.
| | - Martin Schalling
- Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
| | - Martin Ingvar
- Department of Clinical Neuroscience and Osher Center, Karolinska Insitutet, Department of Neuroradiology, Karolinska University Hospital, SE-171 77 Stockholm, Sweden.
| | - Malin Ernberg
- Department of Dental Medicine, Karolinska Institutet, and Scandinavian Center for Orofacial Neurosciences (SCON), SE-141 04 Huddinge, Sweden.
| | - Karin B Jensen
- Department of Clinical Neuroscience and Osher Center, Karolinska Insitutet, Department of Neuroradiology, Karolinska University Hospital, SE-171 77 Stockholm, Sweden.
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Servatius RJ, Marx CE, Sinha S, Avcu P, Kilts JD, Naylor JC, Pang KCH. Brain and Serum Androsterone Is Elevated in Response to Stress in Rats with Mild Traumatic Brain Injury. Front Neurosci 2016; 10:379. [PMID: 27616978 PMCID: PMC4999428 DOI: 10.3389/fnins.2016.00379] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 08/03/2016] [Indexed: 12/03/2022] Open
Abstract
Exposure to lateral fluid percussion (LFP) injury consistent with mild traumatic brain injury (mTBI) persistently attenuates acoustic startle responses (ASRs) in rats. Here, we examined whether the experience of head trauma affects stress reactivity. Male Sprague-Dawley rats were matched for ASRs and randomly assigned to receive mTBI through LFP or experience a sham surgery (SHAM). ASRs were measured post injury days (PIDs) 1, 3, 7, 14, 21, and 28. To assess neurosteroids, rats received a single 2.0 mA, 0.5 s foot shock on PID 34 (S34), PID 35 (S35), on both days (2S), or the experimental context (CON). Levels of the neurosteroids pregnenolone (PREG), allopregnanolone (ALLO), and androsterone (ANDRO) were determined for the prefrontal cortex, hippocampus, and cerebellum. For 2S rats, repeated blood samples were obtained at 15, 30, and 60 min post-stressor for determination of corticosterone (CORT) levels after stress or context on PID 34. Similar to earlier work, ASRs were severely attenuated in mTBI rats without remission for 28 days after injury. No differences were observed between mTBI and SHAM rats in basal CORT, peak CORT levels or its recovery. In serum and brain, ANDRO levels were the most stress-sensitive. Stress-induced ANDRO elevations were greater than those in mTBI rats. As a positive allosteric modulator of gamma-aminobutyric acid (GABAA) receptors, increased brain ANDRO levels are expected to be anxiolytic. The impact of brain ANDRO elevations in the aftermath of mTBI on coping warrants further elaboration.
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Affiliation(s)
- Richard J Servatius
- Department of Veterans Affairs, Syracuse Veterans Affairs Medical CenterSyracuse, NY, USA; Rutgers Biomedical Health Sciences, Stress and Motivated Behavior Institute, Rutgers UniversityNewark, NJ, USA; Graduate School of Biomedical Sciences, Rutgers UniversityNewark, NJ, USA
| | - Christine E Marx
- Veterans Affairs Mid-Atlantic Mental Illness, Research Education and Clinical Center, Durham Veterans Affairs Medical CenterDurham, NC, USA; Department of Psychiatry and Behavioral Sciences, Duke University School of MedicineDurham, NC, USA
| | - Swamini Sinha
- Rutgers Biomedical Health Sciences, Stress and Motivated Behavior Institute, Rutgers UniversityNewark, NJ, USA; Graduate School of Biomedical Sciences, Rutgers UniversityNewark, NJ, USA
| | - Pelin Avcu
- Rutgers Biomedical Health Sciences, Stress and Motivated Behavior Institute, Rutgers UniversityNewark, NJ, USA; Graduate School of Biomedical Sciences, Rutgers UniversityNewark, NJ, USA
| | - Jason D Kilts
- Veterans Affairs Mid-Atlantic Mental Illness, Research Education and Clinical Center, Durham Veterans Affairs Medical CenterDurham, NC, USA; Department of Psychiatry and Behavioral Sciences, Duke University School of MedicineDurham, NC, USA
| | - Jennifer C Naylor
- Veterans Affairs Mid-Atlantic Mental Illness, Research Education and Clinical Center, Durham Veterans Affairs Medical CenterDurham, NC, USA; Department of Psychiatry and Behavioral Sciences, Duke University School of MedicineDurham, NC, USA
| | - Kevin C H Pang
- Rutgers Biomedical Health Sciences, Stress and Motivated Behavior Institute, Rutgers UniversityNewark, NJ, USA; Graduate School of Biomedical Sciences, Rutgers UniversityNewark, NJ, USA; Department of Veterans Affairs, New Jersey Health Care SystemEast Orange, NJ, USA
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49
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Acon-Chen C, Koenig JA, Smith GR, Truitt AR, Thomas TP, Shih TM. Evaluation of acetylcholine, seizure activity and neuropathology following high-dose nerve agent exposure and delayed neuroprotective treatment drugs in freely moving rats. Toxicol Mech Methods 2016; 26:378-88. [PMID: 27329284 DOI: 10.1080/15376516.2016.1197992] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Organophosphorus nerve agents such as soman (GD) inhibit acetylcholinesterase, producing an excess of acetylcholine (ACh), which results in respiratory distress, convulsions and status epilepticus that leads to neuropathology. Several drugs (topiramate, clobazam, pregnanolone, allopregnanolone, UBP 302, cyclopentyladenosine [CPA], ketamine, midazolam and scopolamine) have been identified as potential neuroprotectants that may terminate seizures and reduce brain damage. To systematically evaluate their efficacy, this study employed in vivo striatal microdialysis and liquid chromatography to respectively collect and analyze extracellular ACh in freely moving rats treated with these drugs 20 min after seizure onset induced by a high dose of GD. Along with microdialysis, EEG activity was recorded and neuropathology assessed at 24 h. GD induced a marked increase of ACh, which peaked at 30 min post-exposure to 800% of control levels and then steadily decreased toward baseline levels. Approximately 40 min after treatment, only midazolam (10 mg/kg) and CPA (60 mg/kg) caused a significant reduction of ACh levels, with CPA reducing ACh levels more rapidly than midazolam. Both drugs facilitated a return to baseline levels at least 55 min after treatment. At 24 h, only animals treated with CPA (67%), midazolam (18%) and scopolamine (27%) exhibited seizure termination. While all treatments except for topiramate reduced neuropathology, CPA, midazolam and scopolamine showed the greatest reduction in pathology. Our results suggest that delayed treatment with CPA, midazolam, or scopolamine is effective at reducing GD-induced seizure activity and neuropathology, with CPA and midazolam capable of facilitating a reduction in GD-induced ACh elevation.
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Affiliation(s)
- Cindy Acon-Chen
- a Pharmacology Branch, Research Division , US Army Medical Research Institute of Chemical Defense , MD , USA
| | - Jeffrey A Koenig
- a Pharmacology Branch, Research Division , US Army Medical Research Institute of Chemical Defense , MD , USA
| | - Garrett R Smith
- a Pharmacology Branch, Research Division , US Army Medical Research Institute of Chemical Defense , MD , USA
| | - Amber R Truitt
- a Pharmacology Branch, Research Division , US Army Medical Research Institute of Chemical Defense , MD , USA
| | - Thaddeus P Thomas
- a Pharmacology Branch, Research Division , US Army Medical Research Institute of Chemical Defense , MD , USA
| | - Tsung-Ming Shih
- a Pharmacology Branch, Research Division , US Army Medical Research Institute of Chemical Defense , MD , USA
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50
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Schiller CE, Johnson SL, Abate AC, Schmidt PJ, Rubinow DR. Reproductive Steroid Regulation of Mood and Behavior. Compr Physiol 2016; 6:1135-60. [PMID: 27347888 PMCID: PMC6309888 DOI: 10.1002/cphy.c150014] [Citation(s) in RCA: 121] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In this article, we examine evidence supporting the role of reproductive steroids in the regulation of mood and behavior in women and the nature of that role. In the first half of the article, we review evidence for the following: (i) the reproductive system is designed to regulate behavior; (ii) from the subcellular to cellular to circuit to behavior, reproductive steroids are powerful neuroregulators; (iii) affective disorders are disorders of behavioral state; and (iv) reproductive steroids affect virtually every system implicated in the pathophysiology of depression. In the second half of the article, we discuss the diagnosis of the three reproductive endocrine-related mood disorders (premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression) and present evidence supporting the relevance of reproductive steroids to these conditions. Existing evidence suggests that changes in reproductive steroid levels during specific reproductive states (i.e., the premenstrual phase of the menstrual cycle, pregnancy, parturition, and the menopause transition) trigger affective dysregulation in susceptible women, thus suggesting the etiopathogenic relevance of these hormonal changes in reproductive mood disorders. Understanding the source of individual susceptibility is critical to both preventing the onset of illness and developing novel, individualized treatments for reproductive-related affective dysregulation. © 2016 American Physiological Society. Compr Physiol 6:1135-1160, 2016e.
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Affiliation(s)
- Crystal Edler Schiller
- Psychiatry Department, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Sarah L. Johnson
- Psychiatry Department, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Anna C. Abate
- Psychiatry Department, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Peter J. Schmidt
- Section on Behavioral Endocrinology, National Institute of Mental Health, Department of Health and Human Services, Bethesda, Maryland, USA
| | - David R. Rubinow
- Psychiatry Department, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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