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Psychopharmacology Sep 2016Benzodiazepines are effective anxiolytics, hypnotics, and anticonvulsants but unwanted side effects, including abuse potential, limit their use. A possible strategy to...
RATIONALE
Benzodiazepines are effective anxiolytics, hypnotics, and anticonvulsants but unwanted side effects, including abuse potential, limit their use. A possible strategy to increase the therapeutic index of this drug class is to combine benzodiazepines with neuroactive steroids.
OBJECTIVES
The present study evaluated the extent to which combinations of benzodiazepines (triazolam, clonazepam) and neuroactive steroids (pregnanolone, ganaxolone) induced additive, supra-additive, or infra-additive effects in an elevated zero maze and a drug discrimination procedure in rats.
METHODS
Male Sprague-Dawley rats (N = 7/group) were placed into an elevated zero maze apparatus following injections of multiple doses of triazolam and pregnanolone, alone and combined, or clonazepam and ganaxolone, alone and combined. These drugs/drug combinations also were evaluated in rats (N = 8) trained to discriminate triazolam (0.1 mg/kg, i.p.) from vehicle. Drug interactions were evaluated using isobolographic and dose-addition analysis.
RESULTS
In the elevated zero maze, all drugs engendered dose-dependent increases in time spent in the open quadrant when administered alone. Triazolam and pregnanolone, as well as clonazepam and ganaxolone combinations produced additive or supra-additive effects depending on the fixed-proportion that was tested. In triazolam discrimination, all drugs engendered dose-dependent increases in triazolam-lever responding. In combination, triazolam and pregnanolone and clonazepam and ganaxolone produced predominantly additive discriminative stimulus effects, except for one fixed proportion of clonazepam and ganaxolone which had supra-additive effects.
CONCLUSIONS
Although drug interactions depended on the constituent drugs, the combination tested, and the behavioral endpoint; a combination was identified that would be predicted to result in supra-additive anxiolytic-like effects with predominantly additive discriminative stimulus effects.
Topics: Anesthetics; Animals; Anti-Anxiety Agents; Anxiety; Behavior, Animal; Clonazepam; Discrimination Learning; Drug Interactions; Hypnotics and Sedatives; Male; Pregnanolone; Rats; Rats, Sprague-Dawley; Triazolam
PubMed: 27356519
DOI: 10.1007/s00213-016-4369-8 -
Alcoholism, Clinical and Experimental... Feb 2020For many years, research from around the world has suggested that the neuroactive steroid (3α,5α)-3-hydroxypregnan-20-one (allopregnanolone or 3α,5α-THP) may have... (Review)
Review
For many years, research from around the world has suggested that the neuroactive steroid (3α,5α)-3-hydroxypregnan-20-one (allopregnanolone or 3α,5α-THP) may have therapeutic potential for treatment of various symptoms of alcohol use disorders (AUDs). In this critical review, we systematically address all the evidence that supports such a suggestion, delineate the etiologies of AUDs that are addressed by treatment with allopregnanolone or its precursor pregnenolone, and the rationale for treatment of various components of the disease based on basic science and clinical evidence. This review presents a theoretical framework for understanding how endogenous steroids that regulate the effects of stress, alcohol, and the innate immune system could play a key role in both the prevention and the treatment of AUDs. We further discuss cautions and limitations of allopregnanolone or pregnenolone therapy with suggestions regarding the management of risk and the potential for helping millions who suffer from AUDs.
Topics: Alcoholism; Anesthetics; Animals; Brain; Clinical Trials as Topic; Corticotropin-Releasing Hormone; Humans; Pregnanolone; Receptors, GABA-B; Treatment Outcome
PubMed: 31782169
DOI: 10.1111/acer.14253 -
Psychopharmacology Bulletin Mar 2021ZULRESSO (Brexanolone) is a novel FDA-approved treatment for moderate-to-severe postpartum depression. Postpartum depression may be diagnosed in women experiencing... (Review)
Review
ZULRESSO (Brexanolone) is a novel FDA-approved treatment for moderate-to-severe postpartum depression. Postpartum depression may be diagnosed in women experiencing depressive symptoms which can manifest as cognitive, behavioral, or emotional disturbances as early as the third trimester to 4 weeks following delivery. The efficacy of brexanolone suggests that neurosteroids such as allopregnanolone are important to treat PPD. However, it is currently unclear if brexanolone provides lasting relief of depressive symptoms at or beyond 30 days following administration. Further studies are necessary to make this determination.
Topics: Adult; Depression, Postpartum; Drug Combinations; Female; Humans; Pregnanolone; beta-Cyclodextrins
PubMed: 34092826
DOI: No ID Found -
PloS One 2021The major sites for fast synaptic inhibition in the central nervous system (CNS) are ion channels activated by γ-aminobutyric acid (GABA). These receptors are referred...
BACKGROUND
The major sites for fast synaptic inhibition in the central nervous system (CNS) are ion channels activated by γ-aminobutyric acid (GABA). These receptors are referred as GABA(A) receptors (GABA(A)R). Recent evidence indicates a role of GABA(A)R in modulating the immune response. This work aimed to discern the role of GABA and GABA(A)Rs in human and mouse T cell activity.
METHODS
Mouse splenocytes or human peripheral blood mononuclear cells (PBMCs) were activated with anti-CD3 antibodies and the proliferation of both CD8+ and CD4+ T cells assessed through flow cytometry. Subsequently, the effects on T cell proliferation of either GABA(A)R modulation by diazepam that is also capable of activating mitochondrial based translocator protein (TSPO), alprazolam and allopregnanolone or inhibition by bicucculine methiodide (BMI) and (1,2,5,6-Tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) were assessed.
RESULTS
Positive modulation of GABA(A)Rs either by benzodiazepines or the neurosteroid allopregnanolone inhibits both mouse and human T cell proliferation. GABAergic inhibition of T cell proliferation by benzodiazepines could be rescued by GABA(A)R blocking. Our data suggest that benzodiazepines influence T cell proliferation through both TSPO and GABA(A)Rs activation.
CONCLUSIONS
We conclude that activation of GABA(A)Rs provides immunosuppression by inhibiting T cell proliferation.
Topics: Animals; Benzodiazepines; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Proliferation; Humans; Mice; Pregnanolone; Receptors, GABA; Receptors, GABA-A
PubMed: 34014994
DOI: 10.1371/journal.pone.0251632 -
Drug Design, Development and Therapy 2023Allopregnanolone is a kind of neuroactive steroid or neurosteroid in the central nervous system that acts as an endogenenous GABA receptor positive modulator. However,... (Review)
Review
BACKGROUND
Allopregnanolone is a kind of neuroactive steroid or neurosteroid in the central nervous system that acts as an endogenenous GABA receptor positive modulator. However, at present, no comprehensive bibliometric analysis regarding allopregnanolone research is available. In our study, we intend to analyze the research trends and hot spots related to allopregnanolone in the past 20 years.
METHODS
We searched for allopregnanolone related articles and reviews between 2004 and 2023 from the Web of Science Core Collection database. Then, the bibliometric analysis was conducted using VOSviewer, CiteSpace, Microsoft Excel 2019, as well as the online bibliometric analysis platform (http://bibliometric.com/).
RESULTS
A total of 1841 eligible publications were identified. The number of annual publications and citations was generally on the rise. Among countries, the United States ranked first in overall publications, citations, international cooperation, and the number of research institutions. The University of North Carolina was the most active institution, conducting numerous preclinical and clinical work that focusing on allopregnanolone treatment for diverse psychiatric or neurologic disorders. As for authors, Dr. Frye CA, Morrow AL, and Pinna G were identified as the top three prolific scholars due to their great publications and citations. Based on the publication clusters and citation bursts analysis, the keyword co-occurrence network, the strongest citation bursts, and co-cited references analysis, the hot spots in recent years included "depression", "postpartum depression", "GABA receptor", and so on.
CONCLUSION
Allopregnanolone is still a popular area of research, and the United States leads the way in this area. Dr. Frye CA, Morrow AL, Pinna G, and their teams contributed greatly to the mechanism study and translation study of allopregnanolone. The use of allopregnanolone for the treatment of psychiatric or neurologic disorders, especially postpartum depression, is the current hot spot. However, the underlying mechanisms of anti-depression are still not clear, deserving more in-depth research.
Topics: Female; Humans; Pregnanolone; Bibliometrics; Central Nervous System; Databases, Factual; Depression, Postpartum; Nervous System Diseases
PubMed: 38024537
DOI: 10.2147/DDDT.S434364 -
Biological Psychiatry Aug 2023Chronic stress is a major risk factor for psychiatric illnesses, including depression. However, the pathophysiological mechanisms whereby stress leads to mood disorders...
BACKGROUND
Chronic stress is a major risk factor for psychiatric illnesses, including depression. However, the pathophysiological mechanisms whereby stress leads to mood disorders remain unclear. Allopregnanolone acts as a positive allosteric modulator preferentially on δ subunit-containing GABA (gamma-aminobutyric acid A) receptors. Accumulating clinical and preclinical evidence supports the antidepressant effects of exogenous administration of allopregnanolone analogs; yet, the role of endogenous allopregnanolone in the pathophysiology of depression remains unknown.
METHODS
We utilized a chronic unpredictable stress (CUS) mouse model, followed by behavioral and biochemical assays, to examine whether altered neurosteroid signaling contributes to behavioral outcomes following CUS. We subsequently performed in vivo CRISPR (clustered regularly interspaced short palindromic repeats) knockdown of rate-limiting enzymes involved in allopregnanolone synthesis, 5α-reductase type 1 and 2 (5α1/2), in addition to lentiviral overexpression of 5α1/2 in the basolateral amygdala (BLA) of mice that underwent CUS to assess the impact of 5α1/2 on behavioral outcomes.
RESULTS
The expression of δ subunit-containing GABA receptors and endogenous levels of allopregnanolone were reduced in the BLA following CUS. Treatment with an exogenous allopregnanolone analog, SGE-516, was sufficient to increase allopregnanolone levels in the BLA following CUS. Knockdown of 5α1/2 in the BLA mimicked the behavioral outcomes associated with CUS. Conversely, overexpression of 5α1/2 in the BLA improved behavioral outcomes following CUS.
CONCLUSIONS
Our findings demonstrate that chronic stress impairs endogenous neurosteroid signaling in the BLA, which is sufficient to induce behavioral deficits. Further, these studies suggest that allopregnanolone-based treatments may directly target the underlying pathophysiology of mood disorders suggesting that targeting endogenous neurosteroidogenesis may offer a novel therapeutic strategy.
Topics: Mice; Animals; Pregnanolone; Receptors, GABA-A; Neurosteroids; Signal Transduction; gamma-Aminobutyric Acid
PubMed: 36736870
DOI: 10.1016/j.biopsych.2023.01.022 -
Oxidative Medicine and Cellular... 2019Alzheimer's disease (AD) is the most common form of dementia affecting people mainly in their sixth decade of life and at a higher age. It is an extensively studied... (Review)
Review
Alzheimer's disease (AD) is the most common form of dementia affecting people mainly in their sixth decade of life and at a higher age. It is an extensively studied neurodegenerative disorder yet incurable to date. While its main postmortem brain hallmarks are the presence of amyloid- plaques and hyperphosphorylated tau tangles, the onset of the disease seems to be largely correlated to mitochondrial dysfunction, an early event in the disease pathogenesis. AD is characterized by flawed energy metabolism in the brain and excessive oxidative stress, processes that involve less adenosine triphosphate (ATP) and more reactive oxygen species (ROS) production respectively. Mitochondria are at the center of both these processes as they are responsible for energy and ROS generation through mainly oxidative phosphorylation. Standardized extract (GBE), resveratrol, and phytoestrogens as well as the neurosteroid allopregnanolone have shown not only some mitochondria-modulating properties but also significant antioxidant potential in and studies. According to our review of the literature, GBE, resveratrol, allopregnanolone, and phytoestrogens showed promising effects on mitochondria in a descending evidence order and, notably, this order pattern is in line with the existing clinical evidence level for each entity. In this review, the effects of these four entities are discussed with special focus on their mitochondria-modulating effects and their mitochondria-improving and antioxidant properties across the spectrum of cognitive decline-related disorders. Evidence from preclinical and clinical studies on their mechanisms of action are summarized and highlighted.
Topics: Alzheimer Disease; Animals; Antioxidants; Clinical Trials as Topic; Cognitive Dysfunction; Drug Evaluation, Preclinical; Energy Metabolism; Evidence-Based Medicine; Ginkgo biloba; Humans; Mitochondria; Oxidative Stress; Phytoestrogens; Plant Extracts; Pregnanolone; Resveratrol
PubMed: 31214285
DOI: 10.1155/2019/9695412 -
British Journal of Anaesthesia Jul 1979
Topics: Anesthesia, Intravenous; Anesthetics; Animals; Benzodiazepines; Etomidate; Humans; Kinetics; Midazolam; Phenols; Pregnanolone; Propofol
PubMed: 317793
DOI: 10.1093/bja/51.7.641 -
British Journal of Anaesthesia Feb 1980
Topics: Anesthesia, Intravenous; Anesthetics; Animals; Half-Life; Humans; Kinetics; Pregnanes; Pregnanolone
PubMed: 7378143
DOI: 10.1093/bja/52.2.241-b -
Brain Research Reviews Mar 2008The functions for neurosteroids during development and in response to nervous system injury are beginning to be identified. We focused on a mouse model in which we... (Review)
Review
The functions for neurosteroids during development and in response to nervous system injury are beginning to be identified. We focused on a mouse model in which we believed neurosteroid production would be altered, and which had a neurodegenerative phenotype. Niemann-Pick Type-C (NP-C) is an autosomal recessive neurodegenerative disease caused by mutations in NPC1 (95%) or NPC2 (5%), resulting in lysosomal accumulation of unesterified cholesterol and glycolipids. The NIH mouse model of NP-C has a mutation in the NPC1 gene, and exhibits several pathological features of the most severe NP-C patients. How lysosomal storage and trafficking defects lead to neurodegeneration is unknown. We found that these mice had normal neurosteroidogenic enzyme activity during development, but lost this activity in the early neonatal period, prior to onset of neurological symptoms. Neurons that expressed P450scc, 3beta HSD, as well as those that expressed 3alpha HSD and 5alpha reductase were lost in adult NP-C brains, resulting in diminished concentrations of allopregnanolone. We treated NP-C mice with allopregnanolone and found that a single dose in the neonatal period resulted in a doubling of life span, substantial delay in onset of neurological symptoms, survival of cerebellar Purkinje and granule cell neurons, and reduction in cholesterol and ganglioside accumulation. The mechanism by which allopregnanolone elicited these effects is unknown. Our in vitro studies showed that Purkinje cell survival promoted by allopregnanolone was lost by treatment with bicuculline, suggesting GABA(A) receptors may play a role. We treated NP-C mice with a synthetic GABA(A) neurosteroid, ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one). Ganaxolone treatment of NP-C mice produced beneficial neurological effects, but these effects were not as robust as those obtained using allopregnanolone. Thus, allopregnanolone may elicit its effects through GABA(A) receptors and through other mechanisms. Additional studies also suggest that allopregnanolone may elicit its effects through pregnane-X-receptors (PXR). Our data suggest that mouse models of neurodegeneration may be beneficial in establishing both physiologic and pharmacologic actions of neurosteroids. These animal models further establish the wide range of functions of these compounds, which may ultimately be useful for treatment of human diseases.
Topics: Animals; Disease Models, Animal; Gonadal Steroid Hormones; Humans; Mice; Niemann-Pick Disease, Type C; Pregnanolone; Receptors, GABA-A
PubMed: 17629950
DOI: 10.1016/j.brainresrev.2007.05.012