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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 -
The Journal of Pharmacology and... Jan 2024This article describes recent advances in the use of neurosteroids as novel anticonvulsants for refractory status epilepticus (RSE) and as medical countermeasures (MCs)... (Review)
Review
Neurosteroids as Novel Anticonvulsants for Refractory Status Epilepticus and Medical Countermeasures for Nerve Agents: A 15-Year Journey to Bring Ganaxolone from Bench to Clinic.
This article describes recent advances in the use of neurosteroids as novel anticonvulsants for refractory status epilepticus (RSE) and as medical countermeasures (MCs) for organophosphates and chemical nerve agents (OPNAs). We highlight a comprehensive 15-year journey to bring the synthetic neurosteroid ganaxolone (GX) from bench to clinic. RSE, including when caused by nerve agents, is associated with devastating morbidity and permanent long-term neurologic dysfunction. Although recent approval of benzodiazepines such as intranasal midazolam and intranasal midazolam offers improved control of acute seizures, novel anticonvulsants are needed to suppress RSE and improve neurologic function outcomes. Currently, few anticonvulsant MCs exist for victims of OPNA exposure and RSE. Standard-of-care MCs for postexposure treatment include benzodiazepines, which do not effectively prevent or mitigate seizures resulting from nerve agent intoxication, leaving an urgent unmet medical need for new anticonvulsants for RSE. Recently, we pioneered neurosteroids as next-generation anticonvulsants that are superior to benzodiazepines for treatment of OPNA intoxication and RSE. Because GX and related neurosteroids that activate extrasynaptic GABA-A receptors rapidly control seizures and offer robust neuroprotection by reducing neuronal damage and neuroinflammation, they effectively improve neurologic outcomes after acute OPNA exposure and RSE. GX has been selected for advanced, Biomedical Advanced Research and Development Authority-supported phase 3 trials of RSE and nerve agent seizures. In addition, in mechanistic studies of neurosteroids at extrasynaptic receptors, we identified novel synthetic analogs with features that are superior to GX for current medical needs. Development of new MCs for RSE is complex, tedious, and uncertain due to scientific and regulatory challenges. Thus, further research will be critical to fill key gaps in evaluating RSE and anticonvulsants in vulnerable (pediatric and geriatric) populations and military persons. SIGNIFICANCE STATEMENT: Following organophosphate and nerve agent intoxication, refractory status epilepticus (RSE) occurs despite benzodiazepine treatment. RSE occurs in 40% of status epilepticus patients, with a 35% mortality rate and significant neurological morbidity in survivors. To treat RSE, neurosteroids are better anticonvulsants than benzodiazepines. Our pioneering use of neurosteroids for RSE and nerve agents led us to develop ganaxolone as a novel anticonvulsant and neuroprotectant with significantly improved neurological outcomes. This article describes the bench-to-bedside journey of bringing neurosteroid therapy to patients, with ganaxolone leading the way.
Topics: Humans; Child; Aged; Anticonvulsants; Nerve Agents; Neurosteroids; Midazolam; Medical Countermeasures; Status Epilepticus; Seizures; Benzodiazepines; Organophosphates; Pregnanolone
PubMed: 37977814
DOI: 10.1124/jpet.123.001816 -
Biomolecules Oct 2023Objectives In Vitro: To study the effects of GR3027 (golexanolone) on neurosteroid-induced GABA-mediated current responses under physiological GABAergic conditions with...
Objectives In Vitro: To study the effects of GR3027 (golexanolone) on neurosteroid-induced GABA-mediated current responses under physiological GABAergic conditions with recombinant human α5β3γ2L and α1β2γ2L GABA receptors expressed in human embryonic kidney cells, using the response patch clamp technique combined with the Dynaflow™ application system. With α5β3γ2L receptors, 0.01-3 μM GR3027, in a concentration-dependent manner, reduced the current response induced by 200 nM THDOC + 0.3 µM GABA, as well as the THDOC-induced direct gated effect. GR3027 (1 μM) alone had no effect on the GABA-mediated current response or current in the absence of GABA. With α1β2γ2L receptors, GR3027 alone had no effect on the GABA-mediated current response or did not affect the receptor by itself. Meanwhile, 1-3 µM GR3027 reduced the current response induced by 200 nM THDOC + 30 µM GABA and 3 µM GR3027 that induced by 200 nM THDOC when GABA was not present. Objectives In Vivo: GR3027 reduces allopregnanolone (AP)-induced decreased learning and anesthesia in male Wistar rats. Rats treated i.v. with AP (2.2 mg/kg) or vehicle were given GR3027 in ratios of 1:0.5 to 1:5 dissolved in 10% 2-hydroxypropyl-beta-cyclodextrin. A dose ratio of AP:GR3027 of at least 1:2.5 antagonized the AP-induced decreased learning in the Morris Water Mase (MWM) and 1:7.5 antagonized the loss of righting reflex (LoR). GR3027 treatment did not change other functions in the rat compared to the vehicle group. Conclusions: GR3027 functions in vitro as an inhibitor of GABA receptors holding α5β3γ2L and α1β2γ2L, in vivo, in the rat, as a dose-dependent inhibitor toward AP's negative effects on LoR and learning in the MWM.
Topics: Male; Rats; Humans; Animals; Receptors, GABA-A; GABA Antagonists; Neurosteroids; Rats, Wistar; Pregnanolone; gamma-Aminobutyric Acid
PubMed: 37892178
DOI: 10.3390/biom13101496 -
BioRxiv : the Preprint Server For... Oct 2023Bupropion is an atypical antidepressant and smoking cessation drug which causes adverse effects such as insomnia, irritability, and anxiety. Bupropion inhibits dopamine...
Bupropion is an atypical antidepressant and smoking cessation drug which causes adverse effects such as insomnia, irritability, and anxiety. Bupropion inhibits dopamine and norepinephrine reuptake transporters and eukaryotic cation-conducting pentameric ligand-gated ion channels (pLGICs), such as nicotinic acetylcholine (nACh) and serotonin type 3A (5-HT3A) receptors, at clinically relevant concentrations. However, the binding sites and binding mechanisms of bupropion are still elusive. To further understand the inhibition of pLGICs by bupropion, in this work, using a prokaryotic homologue of pLGICs as a model, we examined the inhibitory potency of bupropion in ligand-gated ion channel (GLIC), a proton-gated ion channel. Bupropion inhibited proton-induced currents in GLIC with an inhibitory potency of 14.9 ± 2.0 μM, comparable to clinically attainable concentrations previously shown to also modulate eukaryotic pLGICs. Using single amino acid substitutions in GLIC and two-electrode voltage-clamp recordings, we further determined a binding site for bupropion in the lower third of the first transmembrane segment M1 at residue T214. The sidechain of M1 T214 together with additional residues of M1 and also of M3 of the adjacent subunit have previously been shown to contribute to binding of other lipophilic molecules like allopregnanolone and pregnanolone.
PubMed: 37873398
DOI: 10.1101/2023.10.09.561596 -
Dialogues in Clinical Neuroscience Dec 2023Postpartum depression has deleterious effects on childbearing persons globally. Existing treatments have been largely extrapolated from those for other forms of... (Review)
Review
Postpartum depression has deleterious effects on childbearing persons globally. Existing treatments have been largely extrapolated from those for other forms of depression and have included pharmacotherapy, psychotherapy, and neuromodulation. Hormonal treatments with oestrogen and progestogens, thought to be a rational approach to treatment in response to an emerging literature on the pathophysiology of postpartum depression, have only limited evidence for efficacy to date. Novel antidepressant development with allopregnanolone analogues, in contrast, has proven a promising avenue for the development of rationally designed and efficacious treatments. This state-of-the-art review presents the evidence for the current standard-of-care pharmacotherapy, hormonal treatment, and emerging allopregnanolone analogues for the treatment of postpartum depression along with a discussion of the current understanding of its neuroactive steroid-driven pathophysiology.
Topics: Female; Humans; Depression, Postpartum; Pregnanolone; Antidepressive Agents; Psychotherapy
PubMed: 37796239
DOI: 10.1080/19585969.2023.2262464 -
The Journal of Pharmacology and... Jan 2024Status epilepticus (SE) is a life-threatening development of self-sustaining seizures that becomes resistant to benzodiazepines when treatment is delayed. Benzodiazepine...
Status epilepticus (SE) is a life-threatening development of self-sustaining seizures that becomes resistant to benzodiazepines when treatment is delayed. Benzodiazepine pharmacoresistance is thought in part to result from internalization of synaptic GABA receptors, which are the main target of the drug. The naturally occurring neurosteroid allopregnanolone is a therapy of interest against SE for its ability to modulate all isoforms of GABA receptors. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been partially effective in combination with benzodiazepines in mitigating SE-associated neurotoxicity. In this study, allopregnanolone as an adjunct to midazolam or midazolam-ketamine combination therapy was evaluated for efficacy against cholinergic-induced SE. Adult male rats implanted with electroencephalographic (EEG) telemetry devices were exposed to the organophosphorus chemical (OP) soman (GD) and treated with an admix of atropine sulfate and HI-6 at 1 minute after exposure followed by midazolam, midazolam-allopregnanolone, or midazolam-ketamine-allopregnanolone 40 minutes after seizure onset. Neurodegeneration, neuronal loss, and neuroinflammation were assessed 2 weeks after GD exposure. Seizure activity, EEG power integral, and epileptogenesis were also compared among groups. Overall, midazolam-ketamine-allopregnanolone combination therapy was effective in reducing cholinergic-induced toxic signs and neuropathology, particularly in the thalamus and hippocampus. Higher dosage of allopregnanolone administered in combination with midazolam and ketamine was also effective in reducing EEG power integral and epileptogenesis. The current study reports that there is a promising potential of neurosteroids in combination with benzodiazepine and ketamine treatments in a GD model of SE. SIGNIFICANCE STATEMENT: Allopregnanolone, a naturally occurring neurosteroid, reduced pathologies associated with soman (GD) exposure such as epileptogenesis, neurodegeneration, and neuroinflammation, and suppressed GD-induced toxic signs when used as an adjunct to midazolam and ketamine in a delayed treatment model of soman-induced status epilepticus (SE) in rats. However, protection was incomplete, suggesting that further studies are needed to identify optimal combinations of antiseizure medications and routes of administration for maximal efficacy against cholinergic-induced SE.
Topics: Rats; Male; Animals; Midazolam; Ketamine; Pregnanolone; Soman; Anticonvulsants; Neuroinflammatory Diseases; Neurosteroids; Status Epilepticus; Seizures; Benzodiazepines; Cholinergic Agents; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 37770198
DOI: 10.1124/jpet.123.001784 -
Biomolecules Aug 2023The pathological consequences of type 2 diabetes mellitus (T2DM) also involve the central nervous system; indeed, T2DM patients suffer from learning and memory...
The pathological consequences of type 2 diabetes mellitus (T2DM) also involve the central nervous system; indeed, T2DM patients suffer from learning and memory disabilities with a higher risk of developing dementia. Although several factors have been proposed as possible contributors, how neuroactive steroids and the gut microbiome impact brain pathophysiology in T2DM remain unexplored. On this basis, in male Zucker diabetic fatty (ZDF) rats, we studied whether T2DM alters memory abilities using the novel object recognition test, neuroactive steroid levels by liquid chromatography-tandem mass spectrometry, hippocampal parameters using molecular assessments, and gut microbiome composition using 16S next-generation sequencing. Results obtained reveal that T2DM worsens memory abilities and that these are correlated with increased levels of corticosterone in plasma and with a decrease in allopregnanolone in the hippocampus, where neuroinflammation, oxidative stress, and mitochondrial dysfunction were reported. Interestingly, our analysis highlighted a small group of taxa strictly related to both memory impairment and neuroactive steroid levels. Overall, the data underline an interesting role for allopregnanolone and microbiota that may represent candidates for the development of therapeutic strategies.
Topics: Humans; Rats; Animals; Male; Rats, Zucker; Gastrointestinal Microbiome; Diabetes Mellitus, Type 2; Neurosteroids; Pregnanolone
PubMed: 37759725
DOI: 10.3390/biom13091325 -
Virologica Sinica Dec 2023Influenza A virus (IAV) poses a global public health concern and remains an imminent threat to human health. Emerging antiviral resistance to the currently approved...
Influenza A virus (IAV) poses a global public health concern and remains an imminent threat to human health. Emerging antiviral resistance to the currently approved influenza drugs emphasizes the urgent need for new therapeutic entities against IAV. Allopregnanolone (ALLO) is a natural product that has been approved as an antidepressant drug. In the present study, we repurposed ALLO as a novel inhibitor against IAVs. Mechanistic studies demonstrated that ALLO inhibited virus replication by interfering with the nucleus translocation of viral nucleoprotein (NP). In addition, ALLO showed significant synergistic activity with compound 16, a hemagglutinin inhibitor of IAVs. In summary, we have identified ALLO as a novel influenza virus inhibitor targeting NP, providing a promising candidate that deserves further investigation as a useful anti-influenza strategy in the future.
Topics: Animals; Dogs; Humans; Nucleoproteins; Pregnanolone; Madin Darby Canine Kidney Cells; Influenza A virus; Influenza, Human; Virus Replication
PubMed: 37741571
DOI: 10.1016/j.virs.2023.09.003 -
Nature Oct 2023Type A γ-aminobutyric acid receptors (GABARs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including...
Type A γ-aminobutyric acid receptors (GABARs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including anaesthetics, sedatives, hypnotics and antidepressants. However, our understanding of GABAR pharmacology has been hindered by the vast number of pentameric assemblies that can be derived from 19 different subunits and the lack of structural knowledge of clinically relevant receptors. Here, we isolate native murine GABAR assemblies containing the widely expressed α1 subunit and elucidate their structures in complex with drugs used to treat insomnia (zolpidem (ZOL) and flurazepam) and postpartum depression (the neurosteroid allopregnanolone (APG)). Using cryo-electron microscopy (cryo-EM) analysis and single-molecule photobleaching experiments, we uncover three major structural populations in the brain: the canonical α1β2γ2 receptor containing two α1 subunits, and two assemblies containing one α1 and either an α2 or α3 subunit, in which the single α1-containing receptors feature a more compact arrangement between the transmembrane and extracellular domains. Interestingly, APG is bound at the transmembrane α/β subunit interface, even when not added to the sample, revealing an important role for endogenous neurosteroids in modulating native GABARs. Together with structurally engaged lipids, neurosteroids produce global conformational changes throughout the receptor that modify the ion channel pore and the binding sites for GABA and insomnia medications. Our data reveal the major α1-containing GABAR assemblies, bound with endogenous neurosteroid, thus defining a structural landscape from which subtype-specific drugs can be developed.
Topics: Animals; Mice; Binding Sites; Cryoelectron Microscopy; Depression, Postpartum; Flurazepam; gamma-Aminobutyric Acid; Hypnotics and Sedatives; Ion Channel Gating; Neurosteroids; Photobleaching; Pregnanolone; Protein Conformation; Protein Subunits; Receptors, GABA-A; Sleep Initiation and Maintenance Disorders; Zolpidem
PubMed: 37730991
DOI: 10.1038/s41586-023-06556-w -
Biomolecules Aug 2023The neurosteroid 3α,5α-THP is a potent GABA receptor-positive modulator and its regulatory action on the HPA axis stress response has been reported in numerous...
The neurosteroid 3α,5α-THP is a potent GABA receptor-positive modulator and its regulatory action on the HPA axis stress response has been reported in numerous preclinical and clinical studies. We previously demonstrated that 3α,5α-THP down-regulation of HPA axis activity during stress is sex-, brain region- and stressor-dependent. In this study, we observed a deleterious submersion behavior in response to 3α,5α-THP (15 mg/kg) during forced swim stress (FSS) that led us to investigate how 3α,5α-THP might affect behavioral coping strategies engaged in by the animal. Given the well-established involvement of the opioid system in HPA axis activation and its interaction with GABAergic neurosteroids, we explored the synergic effects of 3α,5α-THP/opiate system activation in this behavior. Serum β-endorphin (β-EP) was elevated by FSS and enhanced by 3α,5α-THP + FSS. Hypothalamic Mu-opiate receptors (MOP) were increased in female rats by 3α,5α-THP + FSS. Pretreatment with the MOP antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP; 2 mg/kg, IP) reversed submersion behavior in males. Moreover, in both males and females, CTAP pretreatment decreased immobility episodes while increasing immobility duration but did not alter swimming duration. This interaction between 3α,5α-THP and the opioid system in the context of FSS might be important in the development of treatment for neuropsychiatric disorders involving HPA axis activation.
Topics: Female; Male; Animals; Rats; Analgesics, Opioid; Pregnanolone; Hypothalamo-Hypophyseal System; Neurosteroids; Pituitary-Adrenal System; Swimming; Receptors, GABA-A
PubMed: 37627270
DOI: 10.3390/biom13081205