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Biomolecules Feb 2023The neurosteroid allopregnanolone (ALLO) and pregnanolone (PREG), are equally effective positive allosteric modulators (PAMs) of GABA receptors. Interestingly, the PAM...
The neurosteroid allopregnanolone (ALLO) and pregnanolone (PREG), are equally effective positive allosteric modulators (PAMs) of GABA receptors. Interestingly, the PAM effects of ALLO are strongly enantioselective, whereas those of PREG are not. This study was aimed at determining the basis for this difference in enantioselectivity. The oocyte electrophysiology studies showed that -ALLO potentiates GABA-elicited currents in αβ GABA receptors with lower potency and efficacy than ALLO, PREG or -PREG. The small PAM effect of -ALLO was prevented by the α(Q242L) mutation in the intersubunit neurosteroid binding site between the β and α subunits. Consistent with this result, neurosteroid analogue photolabeling with mass spectrometric readout, showed that -ALLO binds weakly to the β-α intersubunit binding site in comparison to ALLO, PREG and -PREG. Rigid body docking predicted that -ALLO binds in the intersubunit site with a preferred orientation 180° different than ALLO, PREG or -PREG, potentially explaining its weak binding and effect. Photolabeling studies did not identify differences between ALLO and -ALLO binding to the α or β intrasubunit binding sites that also mediate neurosteroid modulation of GABA receptors. The results demonstrate that differential binding of -ALLO and -PREG to the β-α intersubunit site accounts for the difference in enantioselectivity between ALLO and PREG.
Topics: Receptors, GABA-A; Neurosteroids; Stereoisomerism; Pregnanolone; gamma-Aminobutyric Acid
PubMed: 36830708
DOI: 10.3390/biom13020341 -
Psychoneuroendocrinology Dec 2009Hormones are trophic factors that integrate central and peripheral nervous system functions, and can influence social, cognitive, emotional and physical (SCEP)... (Review)
Review
Hormones are trophic factors that integrate central and peripheral nervous system functions, and can influence social, cognitive, emotional and physical (SCEP) processes. Greater understanding of behavioral and neurobiological underpinnings of mental, cognitive, and/or physical changes with maturation is becoming increasingly important as the world's population ages. There are individual differences in how people age, but the factors that influence these differences are not well understood. Social supports are one factor that may influence the trajectory of age-related processes. The loss of close relationships, especially among older persons, is one of the greatest risk factors for mental and physical decline. Progesterone, secreted by the ovaries, or produced de novo in the brain, is readily converted centrally to 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), and can influence SCEP, through rapid, non-classical steroid-mediated actions. Our hypothesis is that 3alpha,5alpha-THP is a key trophic factor in SCEP and development. Our research has demonstrated that 3alpha,5alpha-THP facilitates social and sexual behavior of rodents, which evokes further increases in 3alpha,5alpha-THP in midbrain and hippocampus, brain areas involved in SCEP. The role of 3alpha,5alpha-THP to influence social and/or sexual experience, and thereby SCEP, is discussed in this review. Further understanding of these neurobiological and/or behavioral factors may lead to findings that ultimately can promote health and prevent disease.
Topics: Affect; Alzheimer Disease; Animals; Brain; Cognition; Disease Models, Animal; Emotions; Female; Humans; Neurotransmitter Agents; Pregnancy; Pregnanolone; Sexual Behavior, Animal; Social Behavior
PubMed: 19656632
DOI: 10.1016/j.psyneuen.2009.07.005 -
Frontiers in Endocrinology 2020The neurosteroids progesterone and allopregnanolone regulate numerous neuroprotective functions in neural tissues including inhibition of epileptic seizures and cell... (Review)
Review
The neurosteroids progesterone and allopregnanolone regulate numerous neuroprotective functions in neural tissues including inhibition of epileptic seizures and cell death. Many of progesterone's actions are mediated through the nuclear progesterone receptor (PR), while allopregnanolone is widely considered to be devoid of hormonal activity and instead acts through modulation of GABA- receptor activity. However, allopregnanolone can also exert hormonal actions in neuronal cells through binding and activating membrane progesterone receptors (mPRs) belonging to the progestin and adipoQ receptor (PAQR) family. The distribution and functions of the five mPR subtypes (α, β, γ, δ, ε) in neural tissues are briefly reviewed. mPRδ has the highest binding affinity for allopregnanolone and is highly expressed throughout the human brain. Low concentrations (20 nM) of allopregnanolone act through mPRδ to stimulate G protein (G)-dependent signaling pathways resulting in reduced cell death and apoptosis in mPRδ-transfected cells. The 3-methylated synthetic analog of allopregnanolone, ganaxolone, is currently undergoing clinical trials as a promising GABA- receptor-selective antiepileptic drug (AED). New data show that low concentrations (20 nM) of ganaxolone also activate mPRδ signaling and exert anti-apoptotic actions through this receptor. Preliminary evidence suggests that ganaxolone can also exert neuroprotective effects by activating inhibitory G protein (G)-dependent signaling through mPRα and/or mPRβ in neuronal cells. The results indicate that mPRs are likely intermediaries in multiple actions of natural and synthetic neurosteroids in the brain. Potential off-target effects of ganaxolone through activation of mPRs in patients receiving long-term treatment for epilepsy and other disorders should be considered and warrant further investigation.
Topics: Anesthetics; Animals; Apoptosis; Cell Membrane; Epilepsy; Humans; Neurons; Neurosteroids; Pregnanolone; Receptors, Progesterone
PubMed: 32670200
DOI: 10.3389/fendo.2020.00417 -
Cells Sep 2020Neuroinflammation, whose distinctive sign is the activation of microglia, is supposed to play a key role in the development and progression of neurodegenerative...
Neuroinflammation, whose distinctive sign is the activation of microglia, is supposed to play a key role in the development and progression of neurodegenerative diseases. The aim of this investigation was to determine levels of neurosteroids produced by resting and injured BV-2 microglial cells. BV-2 cells were exposed to increasing concentrations of rotenone to progressively reduce their viability by increasing reactive oxygen species (ROS) production. BV-2 cell viability was significantly reduced 24, 48 and 72 h after rotenone (50-1000 nM) exposure. Concomitantly, rotenone (50-100 nM) determined a dose-independent augmentation of ROS production. Then, BV-2 cells were exposed to a single, threshold dose of rotenone (75 nM) to evaluate the overtime release of neurosteroids. In particular, pregnenolone, pregnenolone sulfate, progesterone, 5α-dihydroprogesterone (5α-DHP), allopregnanolone, and pregnanolone, were quantified in the culture medium by liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis. BV-2 cells synthesized all the investigated neurosteroids and, after exposure to rotenone, 5αDHP and pregnanolone production was remarkably increased. In conclusion, we found that BV-2 cells not only synthesize several neurosteroids, but further increase this production following oxidative damage. Pregnanolone and 5α-DHP may play a role in modifying the progression of neuroinflammation in neurodegenerative diseases.
Topics: 5-alpha-Dihydroprogesterone; Animals; Cell Line, Transformed; Cell Survival; Chromatography, Liquid; Mice; Microglia; Pregnanolone; Pregnenolone; Reactive Oxygen Species; Rotenone; Signal Transduction; Tandem Mass Spectrometry
PubMed: 32933155
DOI: 10.3390/cells9092091 -
Journal of Affective Disorders Apr 2024Major depressive disorder (MDD) and postpartum depression (PPD) are disabling conditions. This integrated analysis of MDD and PPD clinical trials investigated the impact... (Randomized Controlled Trial)
Randomized Controlled Trial
The magnitude and sustainability of treatment benefit of zuranolone on function and well-being as assessed by the SF-36 in adult patients with MDD and PPD: An integrated analysis of 4 randomized clinical trials.
BACKGROUND
Major depressive disorder (MDD) and postpartum depression (PPD) are disabling conditions. This integrated analysis of MDD and PPD clinical trials investigated the impact of zuranolone-a positive allosteric modulator of synaptic and extrasynaptic GABA receptors and neuroactive steroid under investigation for adults with MDD and approved as an oral, once-daily, 14-day treatment course for adults with PPD in the US-on health-related quality of life, including functioning and well-being, as assessed using the 36-item Short Form Health Survey V2 (SF-36).
METHODS
Integrated data from 3 MDD (201B, MOUNTAIN, WATERFALL) and 1 PPD trial (ROBIN) for individual SF-36 domains were compared for zuranolone (30- and 50-mg) vs placebo at Day (D)15 and D42. Comparisons between zuranolone responders (≥50 % reduction from baseline in 17-item Hamilton Depression Rating Scale total score) and nonresponders were assessed.
RESULTS
Overall, 1003 patients were included (zuranolone, n = 504; placebo, n = 499). Significant differences in change from baseline (CFB) to D15 for patients in zuranolone vs placebo groups were observed in 6/8 domains; changes were sustained or improved at D42, with significant CFB differences for all 8 domains. Zuranolone responders had significantly higher CFB scores vs nonresponders for all domains at D15 and D42 (p < 0.001).
LIMITATIONS
Two zuranolone doses were integrated across populations of 2 disease states with potential differences in functioning, comorbidities, and patient demographics. All p-values presented are nominal.
CONCLUSIONS
Integrated data across 4 zuranolone clinical trials showed improvements in functioning and well-being across all SF-36 domains. Benefits persisted after completion of treatment course at D42.
Topics: Adult; Female; Humans; Depressive Disorder, Major; Double-Blind Method; Pregnanolone; Pyrazoles; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 38325605
DOI: 10.1016/j.jad.2024.01.268 -
Journal of Anesthesia Apr 2024Neurosteroids (NS) are a class of steroids that are synthesized within the central nervous system (CNS). Various NS can either enhance or inhibit CNS excitability and... (Review)
Review
Neurosteroids (NS) are a class of steroids that are synthesized within the central nervous system (CNS). Various NS can either enhance or inhibit CNS excitability and they play important biological roles in brain development, brain function and as mediators of mood. One class of NS, 3α-hydroxy-pregnane steroids such as allopregnanolone (AlloP) or pregnanolone (Preg), inhibits neuronal excitability; these endogenous NS and their analogues have been therapeutically applied as anti-depressants, anti-epileptics and general anesthetics. While NS have many favorable properties as anesthetics (e.g. rapid onset, rapid recovery, minimal cardiorespiratory depression, neuroprotection), they are not currently in clinical use, largely due to problems with formulation. Recent advances in understanding NS mechanisms of action and improved formulations have rekindled interest in development of NS as sedatives and anesthetics. In this review, the synthesis of NS, and their mechanism of action will be reviewed with specific emphasis on their binding sites and actions on γ-aminobutyric acid type A (GABA) receptors. The potential advantages of NS analogues as sedative and anesthetic agents will be discussed.
Topics: Anesthetics, General; Neurosteroids; Anesthetics; Pregnanolone; gamma-Aminobutyric Acid; Receptors, GABA-A
PubMed: 38252143
DOI: 10.1007/s00540-023-03291-4 -
Neuroendocrinology 2021Neurosteroids modulate epileptic activity by interacting with the γ-aminobutyric acid type A receptor, but their brain levels are still undetermined.
BACKGROUND
Neurosteroids modulate epileptic activity by interacting with the γ-aminobutyric acid type A receptor, but their brain levels are still undetermined.
OBJECTIVES
We aimed to establish neurosteroid levels in the neocortex and hippocampus by liquid chromatography/mass spectrometry in epileptic rats.
METHODS
Kainic acid-treated rats were continuously monitored up to 9 weeks to determine seizure frequency by video electrocorticography (n = 23) and compared to age-matched controls monitored in the same manner (n = 11).
RESULTS
Decreased allopregnanolone (-50%; p < 0.05, Mann-Whitney test) and pregnanolone levels (-64%; p < 0.01) were found in the hippocampus, whereas pregnenolone sulfate, pregnenolone, progesterone, and 5α-dihydroprogesterone were nonsignificantly reduced. No changes were found in the neocortex. Moreover, allopregnanolone (but not pregnanolone) levels were positively correlated with seizure frequency (r2 = 0.4606, p < 0.01).
CONCLUSION
These findings indicate a selective reduction in hippocampal levels of 3α-reduced neurosteroids. This reduction was partially mitigated by seizures in the case of allopregnanolone.
Topics: Animals; Disease Models, Animal; Electrocorticography; Epilepsy; Hippocampus; Male; Neocortex; Pregnanolone; Rats; Rats, Sprague-Dawley; Status Epilepticus
PubMed: 32492675
DOI: 10.1159/000509093 -
Journal of Neuroendocrinology Jan 2020Sleep deprivation (SD) is associated with a broad spectrum of cognitive and behavioural complications, including emotional lability and enhanced stress reactivity, as... (Review)
Review
Sleep deprivation (SD) is associated with a broad spectrum of cognitive and behavioural complications, including emotional lability and enhanced stress reactivity, as well as deficits in executive functions, decision making and impulse control. These impairments, which have profound negative consequences on the health and productivity of many individuals, reflect alterations of the prefrontal cortex (PFC) and its connectivity with subcortical regions. However, the molecular underpinnings of these alterations remain elusive. Our group and others have begun examining how the neurobehavioural outcomes of SD may be influenced by neuroactive steroids, a family of molecules deeply implicated in sleep regulation and the stress response. These studies have revealed that, similar to other stressors, acute SD leads to increased synthesis of the neurosteroid allopregnanolone in the PFC. Whereas this up-regulation is likely aimed at counterbalancing the detrimental impact of oxidative stress induced by SD, the increase in prefrontal allopregnanolone levels contributes to deficits in sensorimotor gating and impulse control, signalling a functional impairment of PFC. This scenario suggests that the synthesis of neuroactive steroids during acute SD may be enacted as a neuroprotective response in the PFC; however, such compensation may in turn set off neurobehavioural complications by interfering with the corticolimbic connections responsible for executive functions and emotional regulation.
Topics: Affect; Animals; Cognitive Dysfunction; Executive Function; Humans; Neurosteroids; Prefrontal Cortex; Pregnanolone; Sleep Deprivation
PubMed: 31505075
DOI: 10.1111/jne.12792 -
JPMA. the Journal of the Pakistan... Mar 2020
Topics: Depression, Postpartum; Drug Combinations; Female; GABA Modulators; Humans; Pregnanolone; beta-Cyclodextrins
PubMed: 32207453
DOI: 10.5455/JPMA.48397 -
Current Alzheimer Research Dec 2007Confronting the efficacy of a regenerative therapeutic is the degenerative environment that is characterized by neuronal loss, physical plague and glial scar barriers... (Review)
Review
Confronting the efficacy of a regenerative therapeutic is the degenerative environment that is characterized by neuronal loss, physical plague and glial scar barriers and inflammation. But perhaps more fundamental from a regenerative perspective, are changes in the biochemical milieu of steroid and peptide growth factors, cytokines and neurotransmitter systems. Data from multiple levels of analysis indicate that gonadal steroid hormones and their metabolites can promote neural health whereas their decline or absence are associated with decline in neural health and increased risk of neurodegenerative disease including Alzheimer's. Among the steroids in decline, is allopregnanolone (APbeta, a neurosteroid metabolite of progesterone, which was found to be reduced in the serum [1,2] and plasma [3] and brain of aged vs. young subjects [4]. Further, Alzheimer disease (AD) victims showed an even further reduction in plasma and brain levels of APalpha relative to age-matched neurologically normal controls [1,4,5]. Our earlier work has shown that APalpha is a neurogenic agent for rodent hippocampal neural progenitors and for human neural progenitor cells derived from the cerebral cortex[6]. Our ongoing research seeks to determine the neurogenic potential of APalpha in the triple transgenic mouse model of Alzheimer's disease (3xTgAD) as AD related pathology progresses from imperceptible to mild to severe. Initial analyses suggest that neurogenic potential changes with age in nontransgenic mice and that the neurogenic profile differs between non-transgenic and 3xTgAD mice. Comparative analyses indicate that APalpha modifies neurogenesis in both nontransgenic and 3xTgAD mice. Preliminary data suggest that APalpha may modify Alzheimer's pathology progression. Together the data indicate that APalpha may maintain the regenerative ability of the brain and modify progression of AD related pathology. Challenges for efficacy of regenerative agents within a degenerative milieu are discussed.
Topics: Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Mice; Mice, Transgenic; Nerve Regeneration; Neuroprotective Agents; Pregnanolone; Rats; tau Proteins
PubMed: 18220513
DOI: 10.2174/156720507783018262