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Pharmacology & Therapeutics Dec 2022Alcohol Use Disorder (AUD) is a multifaceted relapsing disorder that is commonly comorbid with psychiatric disorders, including anxiety. Alcohol exposure produces a... (Review)
Review
Alcohol Use Disorder (AUD) is a multifaceted relapsing disorder that is commonly comorbid with psychiatric disorders, including anxiety. Alcohol exposure produces a plethora of effects on neurobiology. Currently, therapeutic strategies are limited, and only a few treatments - disulfiram, acamprosate, and naltrexone - are available. Given the complexity of this disorder, there is a great need for the identification of novel targets to develop new pharmacotherapy. The GABAergic system, the primary inhibitory system in the brain, is one of the well-known targets for alcohol and is responsible for the anxiolytic effects of alcohol. Interestingly, GABAergic neurotransmission is fine-tuned by neuroactive steroids that exert a regulatory role on several endocrine systems involved in neuropsychiatric disorders including AUD. Mounting evidence indicates that alcohol alters the biosynthesis of neurosteroids, whereas acute alcohol increases and chronic alcohol decreases allopregnanolone levels. Our recent work highlighted that chronic alcohol-induced changes in neurosteroid levels are mediated by epigenetic modifications, e.g., DNA methylation, affecting key enzymes involved in neurosteroid biosynthesis. These changes were associated with changes in GABA receptor subunit expression, suggesting an imbalance between excitatory and inhibitory signaling in AUD. This review will recapitulate the role of neurosteroids in the regulation of the neuroendocrine system, highlight their role in the observed allostatic load in AUD, and develop a framework from mechanisms to potential pharmacotherapy.
Topics: Humans; Pregnanolone; Neurosteroids; Alcoholism; Receptors, GABA-A; Anxiety; Ethanol
PubMed: 36323379
DOI: 10.1016/j.pharmthera.2022.108299 -
Progress in Neurobiology Feb 2014A successful pregnancy requires multiple adaptations in the mother's brain that serve to optimise foetal growth and development, protect the foetus from adverse prenatal... (Review)
Review
A successful pregnancy requires multiple adaptations in the mother's brain that serve to optimise foetal growth and development, protect the foetus from adverse prenatal programming and prevent premature delivery of the young. Pregnancy hormones induce, organise and maintain many of these adaptations. Steroid hormones play a critical role and of particular importance is the progesterone metabolite and neurosteroid, allopregnanolone. Allopregnanolone is produced in increasing amounts during pregnancy both in the periphery and in the maternal and foetal brain. This review critically examines a role for allopregnanolone in both the maternal and foetal brain during pregnancy and development in protecting pregnancy and birth outcomes, with particular emphasis on its role in relation to stress exposure at this time. Late pregnancy is associated with suppressed stress responses. Thus, we begin by considering what is known about the central mechanisms in the maternal brain, induced by allopregnanolone, that protect the foetus(es) from exposure to harmful levels of maternal glucocorticoids as a result of stress during pregnancy. Next we discuss the central mechanisms that prevent premature secretion of oxytocin and consider a role for allopregnanolone in minimising the risk of preterm birth. Allopregnanolone also plays a key role in the foetal brain, where it promotes development and is neuroprotective. Hence we review the evidence about disruption to neurosteroid production in pregnancy, through prenatal stress or other insults, and the immediate and long-term adverse consequences for the offspring. Finally we address whether progesterone or allopregnanolone treatment can rescue some of these deficits in the offspring.
Topics: Animals; Brain; Female; Fetus; Humans; Pregnancy; Pregnancy Outcome; Pregnanolone
PubMed: 24012715
DOI: 10.1016/j.pneurobio.2013.08.005 -
Journal of Neuroendocrinology Feb 2022The rise of ketamine and brexanolone as rapid antidepressant treatments raises the question of common mechanisms. Both drugs act without the long onset time of... (Review)
Review
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.
Topics: Antidepressive Agents; Ketamine; Neurosteroids; Pregnanolone
PubMed: 34423498
DOI: 10.1111/jne.13023 -
Psychoneuroendocrinology Nov 2020Neuroactive steroids (NAS) are derivatives of cholesterol or steroidal precursors made in the gonads, adrenal gland, placenta and brain. We characterized longitudinal...
Longitudinal proneuroactive and neuroactive steroid profiles in medication-free women with, without and at-risk for perinatal depression: A liquid chromatography-tandem mass spectrometry analysis.
BACKGROUND
Neuroactive steroids (NAS) are derivatives of cholesterol or steroidal precursors made in the gonads, adrenal gland, placenta and brain. We characterized longitudinal plasma proneuroactive and NAS in healthy perinatal comparison women (HPCW), women at-risk for perinatal depression (AR-PND), and women with PND with/without comorbid anxiety. We hypothesized that AR-PND women who either did or did not go on to develop PND would have elevated NAS concentrations as compared to HPCW and that NAS would be correlated to depressive and anxiety symptoms.
METHODS
A prospective cohort study evaluated 75 medication-free perinatal women (HPCW, n = 30; AR-PND, n = 19; PND, n = 26). Standardized depression and anxiety assessments and blood samples were completed across 5 visits. Structured Clinical Interviews for DSM-IV TR Disorders were administered at study entry and exit. Plasma pregnenolone, progesterone, 5α- and 5β-dihydroprogesterone, pregnanolone, allopregnanolone, deoxycorticosterone and tetrahydrodeoxycorticosterone were quantified by liquid chromatography-tandem mass spectrometry. Longitudinal relationships between risk-group, depression and anxiety symptoms, and NAS concentrations were analyzed using generalized estimating equations to control for repeated measures correlations.
RESULTS
Perinatal 5α-dihydroprogesterone, 5β-dihydroprogesterone, allopregnanolone, deoxycorticosterone, and tetrahydrodeoxycorticosterone concentrations were higher in AR-PND and PND women compared to HPCW (β = 3.57 ± 1.40 and β = 2.11 ± 1.12, p = 0.03; β = 0.18 ± 0.06 and β = 0.03 ± 0.05, p = 0.02; β = 1.06 ± 0.42 and β = 1.19 ± 0.47, p = 0.01; β = 0.17 ± 0.07 and β = 0.11 ± 0.06, p = 0.05; β = 0.03 ± 0.01 and β = 0.03 ± 0.01, p = 0.05, respectively). Perinatal allopregnanolone, 5α-dihydroprogesterone and tetrahydrodeoxycorticosterone were positively associated with HAM-D (all p < 0.02). HAM-A was positively associated with 5α- and 5β-dihydroprogesterone, pregnanolone, allopregnanolone, deoxycorticosterone and tetrahydrodeoxycorticosterone (all p < 0.05). A history of depression was associated with increased 5α-dihydroprogesterone (2.20 ± 1.09, p = 0.05), deoxycorticosterone (0.13 ± 0.06, p = 0.03) and tetrahydrodeoxycorticosterone (0.03 ± 0.01, p = 0.02).
CONCLUSION
To our knowledge, this study represents the largest prospective study of 5-α and 5-β reductase products of progesterone and deoxycorticosterone in HPCW and women AR-PND. Data suggest that PND is associated with both a reduction of progesterone to 5β-dihydroprogesterone, 5α-dihydroprogesterone, and allopregnanolone, and the 21-hydroxylation to deoxycorticosterone and tetrahydrodeoxycorticosterone. The shift towards 5α-dihydroprogesterone, deoxycorticosterone and tetrahydrodeoxycorticosterone was associated with a history of depression, a significant risk factor for PND.
Topics: 20-alpha-Dihydroprogesterone; Adult; Anxiety; Chromatography, Liquid; Depression; Depression, Postpartum; Depressive Disorder; Desoxycorticosterone; Female; Humans; Longitudinal Studies; Neurosteroids; Parturition; Pregnancy; Pregnanolone; Pregnenolone; Prenatal Care; Progesterone; Prospective Studies; Risk Factors; Tandem Mass Spectrometry
PubMed: 32828068
DOI: 10.1016/j.psyneuen.2020.104827 -
Pharmacology & Therapeutics Oct 2007Neurosteroids are a relatively new class of neuroactive compounds brought to prominence in the past 2 decades. Despite knowing of their presence in the nervous system of... (Review)
Review
Neurosteroids are a relatively new class of neuroactive compounds brought to prominence in the past 2 decades. Despite knowing of their presence in the nervous system of various species for over 20 years and knowing of their functions as GABA(A) and N-methyl-d-aspartate (NMDA) ligands, new and unexpected functions of these compounds are continuously being identified. Absence or reduced concentrations of neurosteroids during development and in adults may be associated with neurodevelopmental, psychiatric, or behavioral disorders. Treatment with physiologic or pharmacologic concentrations of these compounds may also promote neurogenesis, neuronal survival, myelination, increased memory, and reduced neurotoxicity. This review highlights what is currently known about the neurodevelopmental functions and mechanisms of action of 4 distinct neurosteroids: pregnenolone, progesterone, allopregnanolone, and dehydroepiandrosterone (DHEA).
Topics: Animals; Central Nervous System; Dehydroepiandrosterone; Humans; Pregnanolone; Pregnenolone; Progesterone; Steroids; Synaptic Transmission
PubMed: 17651807
DOI: 10.1016/j.pharmthera.2007.04.011 -
Neuroscience and Biobehavioral Reviews Jun 2024Neuroinflammation accompanies several brain disorders, either as a secondary consequence or as a primary cause and may contribute importantly to disease pathogenesis.... (Review)
Review
Neuroinflammation accompanies several brain disorders, either as a secondary consequence or as a primary cause and may contribute importantly to disease pathogenesis. Neurosteroids which act as Positive Steroid Allosteric GABA-A receptor Modulators (Steroid-PAM) appear to modulate neuroinflammation and their levels in the brain may vary because of increased or decreased local production or import from the systemic circulation. The increased synthesis of steroid-PAMs is possibly due to increased expression of the mitochondrial cholesterol transporting protein (TSPO) in neuroinflammatory tissue, and reduced production may be due to changes in the enzymatic activity. Microglia and astrocytes play an important role in neuroinflammation, and their production of inflammatory mediators can be both activated and inhibited by steroid-PAMs and GABA. What is surprising is the finding that both allopregnanolone, a steroid-PAM, and golexanolone, a novel GABA-A receptor modulating steroid antagonist (GAMSA), can inhibit microglia and astrocyte activation and normalize their function. This review focuses on the role of steroid-PAMs in neuroinflammation and their importance in new therapeutic approaches to CNS and liver disease.
Topics: Pregnanolone; Humans; Animals; Neuroinflammatory Diseases; Microglia; Astrocytes; GABA-A Receptor Antagonists
PubMed: 38608826
DOI: 10.1016/j.neubiorev.2024.105668 -
Pharmacology, Biochemistry, and Behavior Jul 2009Adolescent alcohol use may produce long-term changes in the receptors and neurosteroids that putatively mediate alcohol's effects and consequently contribute to alcohol...
Adolescent alcohol use may produce long-term changes in the receptors and neurosteroids that putatively mediate alcohol's effects and consequently contribute to alcohol abuse and dependence as an adult. To test this possibility, ethanol (0.18-1.8 g/kg) and two neurosteroids, pregnanolone (1-10 mg/kg) and dehydroepiandrosterone (DHEA, 1-100 mg/kg), were administered alone and in combination to adult, male Long-Evans rats discriminating 1 g/kg ethanol (15% v/v) under a fixed ratio (FR) 20 schedule of food presentation after adolescent treatment with 15 injections of ethanol (n = 9, 2 g/kg, 20% v/v) or saline (n = 7). When compared as adults, ethanol-treated adolescents (as opposed to saline-treated adolescents) had higher percentages of ethanol-lever responding at doses smaller than the training dose, and higher response rates after both control and ethanol injections. Neither pregnanolone nor DHEA substituted for ethanol in either adolescent-treated group up to doses that substantially decreased response rates. When administered with ethanol, 1 and 3.2 mg/kg of pregnanolone enhanced the discriminative stimulus effects of small ethanol doses more in saline-treated adolescents than in ethanol-treated adolescents. Unlike pregnanolone, 32 and 100 mg/kg of DHEA attenuated the discriminative stimulus effects of ethanol modestly in both adolescent-treated groups. These results in adult rats suggest that adolescent ethanol administration can enhance the discriminative stimulus effects of small ethanol doses and affect the capacity of pregnanolone, but not DHEA, to interact with ethanol's discriminative stimulus effects.
Topics: Adolescent; Adult; Age Factors; Alcoholism; Animals; Dehydroepiandrosterone; Discrimination, Psychological; Ethanol; Humans; Male; Models, Animal; Pregnanolone; Psychology, Adolescent; Rats; Rats, Long-Evans
PubMed: 19393687
DOI: 10.1016/j.pbb.2009.04.012 -
Journal of Neuroendocrinology Feb 2022Forty years into the HIV pandemic, approximately 50% of infected individuals still suffer from a constellation of neurological disorders collectively known as... (Review)
Review
Forty years into the HIV pandemic, approximately 50% of infected individuals still suffer from a constellation of neurological disorders collectively known as 'neuroHIV.' Although combination antiretroviral therapy (cART) has been a tremendous success, in its present form, it cannot eradicate HIV. Reservoirs of virus reside within the central nervous system, serving as sources of HIV virotoxins that damage mitochondria and promote neurotoxicity. Although understudied, there is evidence that HIV or the HIV regulatory protein, trans-activator of transcription (Tat), can dysregulate neurosteroid formation potentially contributing to endocrine dysfunction. People living with HIV commonly suffer from endocrine disorders, including hypercortisolemia accompanied by paradoxical adrenal insufficiency upon stress. Age-related comorbidities often onset sooner and with greater magnitude among people living with HIV and are commonly accompanied by hypogonadism. In the post-cART era, these derangements of the hypothalamic-pituitary-adrenal and -gonadal axes are secondary (i.e., relegated to the brain) and indicative of neuroendocrine dysfunction. We review the clinical and preclinical evidence for neuroendocrine dysfunction in HIV, the capacity for hormone therapeutics to play an ameliorative role and the future steroid-based therapeutics that may have efficacy as novel adjunctives to cART.
Topics: Central Nervous System; HIV Infections; HIV-1; Humans; Neurosecretory Systems; Pregnanolone
PubMed: 34651359
DOI: 10.1111/jne.13047 -
British Journal of Pharmacology Jan 2011Many studies have suggested a relationship between stress, sex steroids, and negative mental and mood changes in humans. The progesterone metabolite allopregnanolone is... (Review)
Review
Many studies have suggested a relationship between stress, sex steroids, and negative mental and mood changes in humans. The progesterone metabolite allopregnanolone is a potent endogenous ligand of the γ-amino butyric acid -A (GABA-A) receptor, and the most discussed neuroactive steroid. Variations in the levels of neuroactive steroids that influence the activity of the GABA-A receptor cause a vulnerability to mental and emotional pathology. There are physiological conditions in which allopregnanolone production increases acutely (e.g. stress) or chronically (e.g. menstrual cycle, pregnancy), thus exposing the GABA-A receptor to high and continuous allopregnanolone concentrations. In such conditions, tolerance to allopregnanolone may develop. We have shown that both acute and chronic tolerances can develop to the effects of allopregnanolone. Following the development of acute allopregnanolone tolerance, there is a decrease in the abundance of the GABA-A receptor α4 subunit and the expression of the α4 subunit mRNA in the ventral-posteriomedial nucleus of the thalamus. Little is known about the mechanism behind allopregnanolone tolerance and its effects on assembly of the GABA-A receptor composition. The exact mechanism of the allopregnanolone tolerance phenomena remains unclear. The purpose of this review is to summarize certain aspects of current knowledge concerning allopregnanolone tolerance and changes in the GABA-A receptors.
Topics: Animals; Drug Tolerance; Female; Gonadal Steroid Hormones; Humans; Pregnancy; Pregnanolone; Progesterone; RNA, Messenger; Rats; Receptors, GABA-A; Stress, Psychological; Substance Withdrawal Syndrome; Time Factors; gamma-Aminobutyric Acid
PubMed: 20883478
DOI: 10.1111/j.1476-5381.2010.01059.x -
Epilepsia Sep 2022Patients with refractory status epilepticus (RSE) have failed treatment with benzodiazepines and ≥1 second-line intravenous (IV) antiseizure medication (ASM)....
OBJECTIVE
Patients with refractory status epilepticus (RSE) have failed treatment with benzodiazepines and ≥1 second-line intravenous (IV) antiseizure medication (ASM). Guidelines recommend IV anesthesia when second-line ASMs have failed, but potential harms can outweigh the benefits. Novel treatments are needed to stop and durably control RSE without escalation to IV anesthetics. Ganaxolone is an investigational neuroactive steroid in development for RSE treatment. This study's objective was to determine the appropriate dosing for IV ganaxolone in RSE and obtain a preliminary assessment of efficacy and safety.
METHODS
This was an open-label, phase 2 trial conducted from February 19, 2018 to September 18, 2019, at three sites in the United States. Patients were aged ≥12 years, had convulsive or nonconvulsive SE, and failed to respond to ≥1 second-line IV ASM. Twenty-one patients were screened; 17 were enrolled. Patients received IV ganaxolone added to standard-of-care ASMs. Ganaxolone infusion was initiated as an IV bolus (over 3 min) with continuous infusion of decreasing infusion rates for 48-96 h followed by an 18-h taper. There were three ganaxolone dosing cohorts: low, 500 mg/day; medium, 650 mg/day; and high, 713 mg/day. The primary end point was the number of patients not requiring escalation to IV anesthetic treatment within 24 h of ganaxolone initiation.
RESULTS
Most of the 17 enrolled patients (65%) had nonconvulsive SE, and had failed a median of three prior ASMs, including first-line benzodiazepine and second-line IV ASM therapy. Median time to SE cessation following ganaxolone initiation was 5 min. No patient required escalation to third-line IV anesthetics during the 24-h period following ganaxolone initiation. Two treatment-related serious adverse events (sedation) were reported. Of the three deaths, none was considered related to ganaxolone; all occurred 9-22 days after completing ganaxolone.
SIGNIFICANCE
IV ganaxolone achieved rapid and durable seizure control in patients with RSE, and showed acceptable safety and tolerability.
Topics: Anesthetics; Anticonvulsants; Benzodiazepines; Humans; Neurosteroids; Pregnanolone; Status Epilepticus
PubMed: 35748707
DOI: 10.1111/epi.17343