Allopregnanolone Explained

Width:225
Width2:225
Alt2:Ball-and-stick model of the allopregnanolone molecule
Usan:brexanolone
Tradename:Zulresso
Dailymedid:Brexanolone
Licence Us:Zulresso
Routes Of Administration:Intravenous
Class:Neurosteroids; Antidepressants
Atc Prefix:N06
Atc Suffix:AX29
Legal Us:Schedule IV
Legal Us Comment:[1]
Bioavailability:Oral

<5%

Protein Bound:>99%
Metabolism:Non-CYP450 (keto-reduction via aldo-keto reductases (AKR), glucuronidation via glucuronosyltransferases (UGT), sulfation via sulfotransferases (SULT))
Elimination Half-Life:9 hours
Excretion:Feces

47%
Urine: 42%

Cas Number:516-54-1
Pubchem:92786
Drugbank:DB11859
Chemspiderid:83760
Unii:S39XZ5QV8Y
Kegg:D11149
Chebi:50169
Chembl:207538
Synonyms:ALLO; ALLOP; SAGE-547; SGE-102; 5α-Pregnan-3α-ol-20-one; 5α-Pregnane-3α-ol-20-one;[2] [3] [4] [5] [6] 3α-Hydroxy-5α-pregnan-20-one; 3α,5α-Tetrahydroprogesterone; 3α,5α-THP
Iupac Name:1-[(3''R'',5''S'',8''R'',9''S'',10''S'',13''S'',14''S'',17''S'')-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1''H''-cyclopenta[''a'']phenanthren-17-yl]ethanone
C:21
H:34
O:2
Smiles:CC(=O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CC[C@@H]4[C@@]3(CC[C@H](C4)O)C)C
Stdinchi:1S/C21H34O2/c1-13(22)17-6-7-18-16-5-4-14-12-15(23)8-10-20(14,2)19(16)9-11-21(17,18)3/h14-19,23H,4-12H2,1-3H3/t14-,15+,16-,17+,18-,19-,20-,21+/m0/s1
Stdinchikey:AURFZBICLPNKBZ-SYBPFIFISA-N

Allopregnanolone is a naturally occurring neurosteroid which is made in the body from the hormone progesterone.[7] As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso,[8] and used to treat postpartum depression.[9] [10] [11] It is given by injection into a vein.[9]

Side effects of brexanolone may include sedation, sleepiness, dry mouth, hot flashes, and loss of consciousness. It is a neurosteroid and acts as a positive allosteric modulator of the GABAA receptor, the major biological target of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).[12]

Brexanolone was approved for medical use in the United States in 2019.[13] The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[14] The long administration time, as well as the cost for a one-time treatment, have raised concerns about accessibility for many women.[15]

Medical uses

Brexanolone is used to treat postpartum depression in adult women, administered as a continuous intravenous infusion over a period of 60 hours.[9] [16]

Clinical efficacy

Women experiencing moderate to severe postpartum depression when treated with a single dose of intravenous brexanolone display a significant reduction in HAM-D scores which persisted 30 days post-treatment.[17]

Side effects

Side effects of brexanolone include dizziness (10–20%), sedation (13–21%), headache (18%), nausea (10%), dry mouth (3–11%), loss of consciousness (3–5%), and flushing (2–5%).[18] It can produce euphoria to a degree similar to that of alprazolam (3–13% at infusion doses of 90–270 μg over a one-hour period). Serious or severe adverse effects are rare but may include altered state of consciousness, syncope, presyncope, fatigue, and insomnia.[18]

Biological function

Allopregnanolone possesses a wide variety of effects, including, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding,[19] prosocial,[20] antiaggressive,[21] prosexual, sedative, pro-sleep,[22] cognitive, memory-impairment, analgesic,[23] anesthetic, anticonvulsant, neuroprotective, and neurogenic effects. Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of mood, anxiety, premenstrual syndrome, catamenial epilepsy, and various other neuropsychiatric conditions.[24] [25] [26]

During pregnancy, allopregnanolone and pregnanolone are involved in sedation and anesthesia of the fetus.[27] [28]

Allopregnanolone is a metabolic intermediate in an androgen backdoor pathway from progesterone to dihydrotestosterone, which occurs during normal male fetus development; placental progesterone in the male fetus is the feedstock of this pathway; deficiencies in this pathway lead to insufficient virilization of the male fetus.[29]

Mechanism of action

Molecular interactions

Allopregnanolone is an endogenous inhibitory pregnane neurosteroid.[7] It is made from pregnenolone, and is a positive allosteric modulator of the action of γ-aminobutyric acid (GABA) at GABAA receptor. Allopregnanolone has effects similar to those of other positive allosteric modulators of the GABA action at GABAA receptor such as the benzodiazepines, including anxiolytic, sedative, and anticonvulsant activity.[30] [31] Endogenously produced allopregnanolone exerts a neurophysiological role by fine-tuning of GABAA receptor and modulating the action of several positive allosteric modulators and agonists at GABAA receptor.[32]

Allopregnanolone acts as a highly potent positive allosteric modulator of the GABAA receptor. While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABAA receptor isoforms, those isoforms containing δ subunits exhibit the greatest potentiation.[33] Allopregnanolone has also been found to act as a positive allosteric modulator of the GABAA-ρ receptor, though the implications of this action are unclear.[34] [35] In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be a negative allosteric modulator of nACh receptors,[36] and also appears to act as a negative allosteric modulator of the 5-HT3 receptor.[37] Along with the other inhibitory neurosteroids, allopregnanolone appears to have little or no action at other ligand-gated ion channels, including the NMDA, AMPA, kainate, and glycine receptors.[38]

Unlike progesterone, allopregnanolone is inactive at the classical nuclear progesterone receptor (PR). However, allopregnanolone can be intracellularly oxidized into 5α-dihydroprogesterone, which does act as an agonist of the PR, and for this reason, allopregnanolone can produce PR-mediated progestogenic effects.[39] [40] (5α-dihydroprogesterone is reduced to produce allopregnanolone, and progesterone is reduced to produce 5α-dihydroprogesterone). In addition, allopregnanolone was reported in 2012 to be an agonist of the membrane progesterone receptors (mPRs) discovered shortly before, including mPRδ, mPRα, and mPRβ, with its activity at these receptors about a magnitude more potent than at the GABAA receptor.[41] [42] The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective and antigonadotropic properties.[43] Also like progesterone, recent evidence has shown that allopregnanolone is an activator of the pregnane X receptor.[44]

Similarly to many other GABAA receptor positive allosteric modulators, allopregnanolone has been found to act as an inhibitor of L-type voltage-gated calcium channels (L-VGCCs),[45] including α1 subtypes Cav1.2 and Cav1.3.[46] However, the threshold concentration of allopregnanolone to inhibit L-VGCCs was determined to be 3 μM (3,000 nM), which is far greater than the concentration of 5 nM that has been estimated to be naturally produced in the human brain. Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone. Also, allopregnanolone, along with several other neurosteroids, has been found to activate the G protein-coupled bile acid receptor (GPBAR1, or TGR5).[47] However, it is only able to do so at micromolar concentrations, which, similarly to the case of the L-VGCCs, are far greater than the low nanomolar concentrations of allopregnanolone estimated to be present in the brain.

Biphasic actions at the GABAA receptor

Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety, irritability, and aggression.[48] [49] [50] This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABAA receptor – moderate level increases (in the range of 1.5–2 nmol/L total allopregnanolone, which are approximately equivalent to luteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it. This seems to be a common effect of many GABAA receptor positive allosteric modulators. In accordance, acute administration of low doses of micronized progesterone (which reliably elevates allopregnanolone levels) has been found to have negative effects on mood, while higher doses have a neutral effect.[51]

Antidepressant effects

The mechanism by which neurosteroid GABAA receptor PAMs like brexanolone have antidepressant effects is unknown.[52] Other GABAA receptor PAMs, such as benzodiazepines, are not thought of as antidepressants and have no proven efficacy, although alprazolam has historically been prescribed for depression.[53] [54] Neurosteroid GABAA receptor PAMs are known to interact with GABAA receptors and subpopulations differently than benzodiazepines. GABAA receptor-potentiating neurosteroids may preferentially target δ-subunit–containing GABAA receptors, and enhance both tonic and phasic inhibition mediated by GABAA receptors. It is possible that neurosteroids like allopregnanolone may act on other targets, including membrane progesterone receptors, T-type voltage-gated calcium channels, and others, to mediate antidepressant effects.

Pharmacology

Pharmacokinetics

Brexanolone has low oral bioavailability of less than 5%, necessitating non-oral administration.[55] The volume of distribution of brexanolone is approximately 3 L/kg. Its plasma protein binding is more than 99%. Brexanolone is metabolized by keto-reduction mediated via aldo-keto reductases. The compound is conjugated by glucuronidation via glucuronosyltransferases and sulfation via sulfotransferases. It is not metabolized significantly by the cytochrome P450 system. The three main metabolites of brexanolone are inactive. The elimination half-life of brexanolone is nine hours. Its total plasma clearance is 1 L/h/kg. It is excreted 47% in feces and 42% in urine. Less than 1% is excreted as unchanged brexanolone.

Chemistry

See also: List of neurosteroids.

Allopregnanolone is a pregnane (C21) steroid and is also known as 5α-pregnan-3α-ol-20-one, 5α-pregnane-3α-ol-20-one,[2] [3] [4] [5] [6] 3α-hydroxy-5α-pregnan-20-one, or 3α,5α-tetrahydroprogesterone (3α,5α-THP). It is closely related structurally to 5-pregnenolone (pregn-5-en-3β-ol-20-dione), progesterone (pregn-4-ene-3,20-dione), the isomers of pregnanedione (5-dihydroprogesterone; 5-pregnane-3,20-dione), the isomers of 4-pregnenolone (3-dihydroprogesterone; pregn-4-en-3-ol-20-one), and the isomers of pregnanediol (5-pregnane-3,20-diol). In addition, allopregnanolone is one of four isomers of pregnanolone (3,5-tetrahydroprogesterone), with the other three isomers being pregnanolone (5β-pregnan-3α-ol-20-one), isopregnanolone (5α-pregnan-3β-ol-20-one), and epipregnanolone (5β-pregnan-3β-ol-20-one).

Biosynthesis

The biosynthesis of allopregnanolone in the brain starts with the conversion of progesterone into 5α-dihydroprogesterone by 5α-reductase. After that, 3α-hydroxysteroid dehydrogenase converts this intermediate into allopregnanolone. Allopregnanolone in the brain is produced by cortical and hippocampus pyramidal neurons and pyramidal-like neurons of the basolateral amygdala.[56]

Derivatives

A variety of synthetic derivatives and analogues of allopregnanolone with similar activity and effects exist, including alfadolone (3α,21-dihydroxy-5α-pregnane-11,20-dione), alfaxolone (3α-hydroxy-5α-pregnane-11,20-dione), ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), hydroxydione (21-hydroxy-5β-pregnane-3,20-dione), minaxolone (11α-(dimethylamino)-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one), Org 20599 (21-chloro-3α-hydroxy-2β-morpholin-4-yl-5β-pregnan-20-one), Org 21465 (2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-yl methanesulfonate), and renanolone (3α-hydroxy-5β-pregnan-11,20-dione).

The 21-hydroxylated derivative of this compound, tetrahydrodeoxycorticosterone, is an endogenous inhibitory neurosteroid with similar properties to those of allopregnanolone, and the 3β-methyl analogue of allopregnanolone, ganaxolone, is under development to treat epilepsy and other conditions, including post-traumatic stress disorder.

History

In March 2019, brexanolone was approved in the United States for the treatment of postpartum depression (PPD) in adult women, the first drug approved by the U.S. Food and Drug Administration (FDA) specifically for PPD.

The efficacy of brexanolone was shown in two clinical studies of participants who received a 60-hour continuous intravenous infusion of brexanolone or placebo and were then followed for four weeks. The FDA approved allopregnanolone based on evidence from three clinical trials, conducted in the United States, (Trial 1/NCT02942004, Trial 3/NCT02614541, Trial 2/ NCT02942017) of 247 women with moderate or severe postpartum depression.[57]

The FDA granted the application for brexanolone priority review and breakthrough therapy designations, and granted approval of Zulresso to Sage Therapeutics, Inc.

Society and culture

Names

Brexanolone is both the International Nonproprietary Name and the United States Adopted Name in the context of its use as a medication.[58] [59]

Zulresso is a brand name of the medication.

Legal status

In the United States, brexanolone is a Schedule IV controlled substance.

Available forms

Brexanolone is an aqueous mixture of synthetic allopregnanolone and sulfobutyl ether β-cyclodextrin (betadex sulfobutyl ether sodium), a solubilizing agent. It is provided at an allopregnanolone concentration of 100 mg/20 mL (5 mg/mL) in single-dose vials for use by intravenous infusion. Each mL of brexanolone solution contains 5 mg allopregnanolone, 250 mg sulfobutyl ether β-cyclodextrin, 0.265 mg citric acid monohydrate, 2.57 mg sodium citrate dihydrate, and water for injection. The solution is hypertonic and must be diluted to a target concentration of 1 mg/mL with sterile water and sodium chloride prior to administration. Five infusion bags are generally required for the full infusion. More than five infusion bags are necessary for patients weighing more than 90 kg (200 lbs).

Research

Brexanolone was under development as an intravenously administered medication for the treatment of major depressive disorder, super-refractory status epilepticus, and essential tremor, but development for these indications was discontinued.[60]

It has been suggested that allopregnanolone and its precursor pregnenolone may have therapeutic potential for treatment of various symptoms of alcohol use disorders by restoring deficits in GABAergic inhibition, moderating corticotropin releasing factor (CRF) signaling, and inhibiting excessive neuroimmune activation. Many co-occurring symptoms of ethanol addiction (e.g., anxiety, depression, seizures, sleep disturbance, pain) that are believed to contribute to the downward spiral of the addiction may also be controlled with neuroactive steroids.[61]

Exogenous progesterone, such as oral progesterone, elevates allopregnanolone levels in the body with good dose-to-serum level correlations.[62] Due to this, it has been suggested that oral progesterone could be described as a prodrug of sorts for allopregnanolone. As a result, there has been some interest in using oral progesterone to treat catamenial epilepsy,[63] as well as other menstrual cycle-related and neurosteroid-associated conditions. In addition to oral progesterone, oral pregnenolone has also been found to act as a prodrug of allopregnanolone,[64] [65] [66] though also of pregnenolone sulfate.[67]

In animal models of traumatic brain injury, allopregnanolone has been shown to reduce inflammation by attenuating the production of proinflammatory cytokines (IL-1β and TNF-α) at 3 h after the injury. It has also been shown to reduce the severity of brain damage and improve cognitive function and recovery.[68]

Further reading

Notes and References

  1. Web site: DEA Schedules Postpartum Depression Treatment Zulresso . Monthly Prescribing Reference . 17 June 2019 . https://web.archive.org/web/20190903150157/https://www.empr.com/home/news/dea-schedules-postpartum-depression-treatment-zulresso/ . 3 September 2019 . live . 24 November 2019.
  2. September 1990 . 5α-Pregnane-3α-ol-20-one Identified as an Active Molecular Species of Steroid Anesthetic in Brain . 10.1097/00000542-199009001-00702 . Krieger NR, Mok WM, Herschkowitz S . Anesthesiology . 73. free . doi .
  3. Yagen B, Gallili GE, Mateles RI . Progesterone biotransformation by plant cell suspension cultures . Applied and Environmental Microbiology . 36 . 2 . 213–216 . August 1978 . 697360 . 291203 . 10.1128/AEM.36.2.213-216.1978 . 1978ApEnM..36..213Y .
  4. Meyer HH, Jewgenow K, Hodges JK . Binding activity of 5alpha-reduced gestagens to the progestin receptor from African elephant (Loxodonta africana) . General and Comparative Endocrinology . 105 . 2 . 164–167 . February 1997 . 9038248 . 10.1006/gcen.1996.6813 .
  5. Frye C, Seliga A . Olanzapine and progesterone have dose-dependent and additive effects to enhance lordosis and progestin concentrations of rats . Physiology & Behavior . 76 . 1 . 151–158 . May 2002 . 12175598 . 10.1016/s0031-9384(02)00689-3 . 38249308 .
  6. Mahendroo M, Wilson JD, Richardson JA, Auchus RJ . Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways . Molecular and Cellular Endocrinology . 222 . 1–2 . 113–120 . July 2004 . 15249131 . 10.1016/j.mce.2004.04.009 . 54297812 .
  7. Book: Reddy DS . Sex Differences in the Human Brain, their Underpinnings and Implications . Neurosteroids . Progress in Brain Research . 186 . 113–137 . 2010 . Elsevier . 21094889 . 3139029 . 10.1016/B978-0-444-53630-3.00008-7 . 9780444536303 .
  8. Web site: ChemIDplus - 516-54-1 - AURFZBICLPNKBZ-SYBPFIFISA-N - Brexanolone [USAN] - Similar structures search, synonyms, formulas, resource links, and other chemical information.]. NIH Toxnet. 26 December 2017.
  9. FDA approves first treatment for post-partum depression . U.S. Food and Drug Administration (FDA) . 19 March 2019 . https://web.archive.org/web/20191011120005/https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-post-partum-depression . 11 October 2019 . live . 21 March 2019 .
  10. Frieder A, Fersh M, Hainline R, Deligiannidis KM . Pharmacotherapy of Postpartum Depression: Current Approaches and Novel Drug Development . CNS Drugs . 33 . 3 . 265–282 . March 2019 . 30790145 . 6424603 . 10.1007/s40263-019-00605-7 .
  11. Wilkinson ST, Sanacora G . A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems . Drug Discovery Today . 24 . 2 . 606–615 . February 2019 . 30447328 . 6397075 . 10.1016/j.drudis.2018.11.007 .
  12. Web site: Zulresso- brexanolone injection, solution . . 18 November 2019 . 23 November 2019.
  13. Web site: Drug Approval Package: Zulresso . U.S. Food and Drug Administration (FDA) . 7 February 2019 . 6 August 2020.
  14. Web site: New Drug Therapy Approvals 2019 . U.S. Food and Drug Administration . 31 December 2019 . 15 September 2020.
  15. News: Chatterjee R . New Postpartum Depression Drug Could Be Hard To Access For Moms Most In Need . . 21 March 2019 . 22 March 2019 .
  16. Web site: Zulresso (brexanolone) dosing, indications, interactions, adverse effects, and more . 2023-09-30 . reference.medscape.com.
  17. Edinoff AN, Odisho AS, Lewis K, Kaskas A, Hunt G, Cornett EM, Kaye AD, Kaye A, Morgan J, Barrilleaux PS, Lewis D, Viswanath O, Urits I . 6 . Brexanolone, a GABAA Modulator, in the Treatment of Postpartum Depression in Adults: A Comprehensive Review . Frontiers in Psychiatry . 12 . 699740 . 2021 . 34594247 . 8477036 . 10.3389/fpsyt.2021.699740 . free .
  18. Walkery A, Leader LD, Cooke E, VandenBerg A . Review of Allopregnanolone Agonist Therapy for the Treatment of Depressive Disorders . English . Drug Design, Development and Therapy . 15 . 3017–3026 . 2021-07-09 . 34267503 . 8276990 . 10.2147/DDDT.S240856 . free .
  19. Rougé-Pont F, Mayo W, Marinelli M, Gingras M, Le Moal M, Piazza PV . The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens . The European Journal of Neuroscience . 16 . 1 . 169–173 . July 2002 . 12153544 . 10.1046/j.1460-9568.2002.02084.x . 9953445 .
  20. Frye CA . Neurosteroids' effects and mechanisms for social, cognitive, emotional, and physical functions . Psychoneuroendocrinology . 34 . Suppl 1 . S143–S161 . December 2009 . 19656632 . 2898141 . 10.1016/j.psyneuen.2009.07.005 .
  21. Pinna G, Costa E, Guidotti A . Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior . Proceedings of the National Academy of Sciences of the United States of America . 102 . 6 . 2135–2140 . February 2005 . 15677716 . 548579 . 10.1073/pnas.0409643102 . free . 2005PNAS..102.2135P . doi .
  22. Terán-Pérez G, Arana-Lechuga Y, Esqueda-León E, Santana-Miranda R, Rojas-Zamorano JÁ, Velázquez Moctezuma J . Steroid hormones and sleep regulation . Mini Reviews in Medicinal Chemistry . 12 . 11 . 1040–1048 . October 2012 . 23092405 . 10.2174/138955712802762167 .
  23. Patte-Mensah C, Meyer L, Taleb O, Mensah-Nyagan AG . Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain . Progress in Neurobiology . 113 . 70–78 . February 2014 . 23948490 . 10.1016/j.pneurobio.2013.07.004 . 207407077 .
  24. Bäckström T, Andersson A, Andreé L, Birzniece V, Bixo M, Björn I, Haage D, Isaksson M, Johansson IM, Lindblad C, Lundgren P, Nyberg S, Odmark IS, Strömberg J, Sundström-Poromaa I, Turkmen S, Wahlström G, Wang M, Wihlbäck AC, Zhu D, Zingmark E . 6 . Pathogenesis in menstrual cycle-linked CNS disorders . Annals of the New York Academy of Sciences . 1007 . 1 . 42–53 . December 2003 . 14993039 . 10.1196/annals.1286.005 . 20995334 . 2003NYASA1007...42B . free .
  25. Guille C, Spencer S, Cavus I, Epperson CN . The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: implications for diagnosis and treatment . Epilepsy & Behavior . 13 . 1 . 12–24 . July 2008 . 18346939 . 4112568 . 10.1016/j.yebeh.2008.02.004 .
  26. Finocchi C, Ferrari M . Female reproductive steroids and neuronal excitability . Neurological Sciences . 32 . Suppl 1 . S31–S35 . May 2011 . 21533709 . 10.1007/s10072-011-0532-5 . 8885335 .
  27. Mellor DJ, Diesch TJ, Gunn AJ, Bennet L . The importance of 'awareness' for understanding fetal pain . Brain Research. Brain Research Reviews . 49 . 3 . 455–471 . November 2005 . 16269314 . 10.1016/j.brainresrev.2005.01.006 . 9833426 .
  28. Lagercrantz H, Changeux JP . The emergence of human consciousness: from fetal to neonatal life . Pediatric Research . 65 . 3 . 255–260 . March 2009 . 19092726 . 10.1203/PDR.0b013e3181973b0d . [...] the fetus is sedated by the low oxygen tension of the fetal blood and the neurosteroid anesthetics pregnanolone and the sleep-inducing prostaglandin D2 provided by the placenta (36). . 39391626 . free . doi .
  29. 10.15347/WJM/2023.003 . free . Alternative androgen pathways . 2023 . Masiutin M, Yadav M . WikiJournal of Medicine . 10 . X . 257943362.
  30. Reddy DS, Rogawski MA, Rogawski MA, Olsen RW, Delgado-Escueta AV, Reddy DS, Rogawski MA . Neurosteroids — Endogenous Regulators of Seizure Susceptibility and Role in the Treatment of Epilepsy . Jasper's Basic Mechanisms of the Epilepsies, 4th Edition . 984–1002 . 2012 . 22787590 . 10.1093/med/9780199746545.003.0077 . 9780199746545 .
  31. Kokate TG, Svensson BE, Rogawski MA . Anticonvulsant activity of neurosteroids: correlation with gamma-aminobutyric acid-evoked chloride current potentiation . The Journal of Pharmacology and Experimental Therapeutics . 270 . 3 . 1223–1229 . September 1994 . 7932175 .
  32. Pinna G, Uzunova V, Matsumoto K, Puia G, Mienville JM, Costa E, Guidotti A . Brain allopregnanolone regulates the potency of the GABA(A) receptor agonist muscimol . Neuropharmacology . 39 . 3 . 440–448 . January 2000 . 10698010 . 10.1016/S0028-3908(99)00149-5 . 42753647 .
  33. Nik AM, Pressly B, Singh V, Antrobus S, Hulsizer S, Rogawski MA, Wulff H, Pessah IN . 6 . Rapid Throughput Analysis of GABAA Receptor Subtype Modulators and Blockers Using DiSBAC1(3) Membrane Potential Red Dye . Molecular Pharmacology . 92 . 1 . 88–99 . July 2017 . 28428226 . 5452057 . 10.1124/mol.117.108563 .
  34. Morris KD, Moorefield CN, Amin J . Differential modulation of the gamma-aminobutyric acid type C receptor by neuroactive steroids . Molecular Pharmacology . 56 . 4 . 752–759 . October 1999 . 10496958 .
  35. Li W, Jin X, Covey DF, Steinbach JH . Neuroactive steroids and human recombinant rho1 GABAC receptors . The Journal of Pharmacology and Experimental Therapeutics . 323 . 1 . 236–247 . October 2007 . 17636008 . 3905684 . 10.1124/jpet.107.127365 . 12294587 .
  36. Bullock AE, Clark AL, Grady SR, Robinson SF, Slobe BS, Marks MJ, Collins AC . Neurosteroids modulate nicotinic receptor function in mouse striatal and thalamic synaptosomes . Journal of Neurochemistry . 68 . 6 . 2412–2423 . June 1997 . 9166735 . 10.1046/j.1471-4159.1997.68062412.x . 26195479 .
  37. Wetzel CH, Hermann B, Behl C, Pestel E, Rammes G, Zieglgänsberger W, Holsboer F, Rupprecht R . 6 . Functional antagonism of gonadal steroids at the 5-hydroxytryptamine type 3 receptor . Molecular Endocrinology . 12 . 9 . 1441–1451 . September 1998 . 9731711 . 10.1210/mend.12.9.0163 . free . doi .
  38. Mellon SH . Neurosteroid regulation of central nervous system development . Pharmacology & Therapeutics . 116 . 1 . 107–124 . October 2007 . 17651807 . 2386997 . 10.1016/j.pharmthera.2007.04.011 .
  39. Rupprecht R, Reul JM, Trapp T, van Steensel B, Wetzel C, Damm K, Zieglgänsberger W, Holsboer F . 6 . Progesterone receptor-mediated effects of neuroactive steroids . Neuron . 11 . 3 . 523–530 . September 1993 . 8398145 . 10.1016/0896-6273(93)90156-l . 11205767 .
  40. Reddy DS, Estes WA . Clinical Potential of Neurosteroids for CNS Disorders . Trends in Pharmacological Sciences . 37 . 7 . 543–561 . July 2016 . 27156439 . 5310676 . 10.1016/j.tips.2016.04.003 .
  41. Thomas P, Pang Y . Membrane progesterone receptors: evidence for neuroprotective, neurosteroid signaling and neuroendocrine functions in neuronal cells . Neuroendocrinology . 96 . 2 . 162–171 . 2012 . 22687885 . 3489003 . 10.1159/000339822 .
  42. Pang Y, Dong J, Thomas P . Characterization, neurosteroid binding and brain distribution of human membrane progesterone receptors δ and (mPRδ and mPR) and mPRδ involvement in neurosteroid inhibition of apoptosis . Endocrinology . 154 . 1 . 283–295 . January 2013 . 23161870 . 3529379 . 10.1210/en.2012-1772 .
  43. Sleiter N, Pang Y, Park C, Horton TH, Dong J, Thomas P, Levine JE . Progesterone receptor A (PRA) and PRB-independent effects of progesterone on gonadotropin-releasing hormone release . Endocrinology . 150 . 8 . 3833–3844 . August 2009 . 19423765 . 2717864 . 10.1210/en.2008-0774 .
  44. Lamba V, Yasuda K, Lamba JK, Assem M, Davila J, Strom S, Schuetz EG . PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators . Toxicology and Applied Pharmacology . 199 . 3 . 251–265 . September 2004 . 15364541 . 10.1016/j.taap.2003.12.027 . 2004ToxAP.199..251L .
  45. Hu AQ, Wang ZM, Lan DM, Fu YM, Zhu YH, Dong Y, Zheng P . Inhibition of evoked glutamate release by neurosteroid allopregnanolone via inhibition of L-type calcium channels in rat medial prefrontal cortex . Neuropsychopharmacology . 32 . 7 . 1477–1489 . July 2007 . 17151597 . 10.1038/sj.npp.1301261 . free . doi .
  46. Earl DE, Tietz EI . Inhibition of recombinant L-type voltage-gated calcium channels by positive allosteric modulators of GABAA receptors . The Journal of Pharmacology and Experimental Therapeutics . 337 . 1 . 301–311 . April 2011 . 21262851 . 3063747 . 10.1124/jpet.110.178244 .
  47. Keitel V, Görg B, Bidmon HJ, Zemtsova I, Spomer L, Zilles K, Häussinger D . The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain . Glia . 58 . 15 . 1794–1805 . November 2010 . 20665558 . 10.1002/glia.21049 . 37368754 .
  48. Bäckström T, Haage D, Löfgren M, Johansson IM, Strömberg J, Nyberg S, Andréen L, Ossewaarde L, van Wingen GA, Turkmen S, Bengtsson SK . 6 . Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons . Neuroscience . 191 . 46–54 . September 2011 . 21600269 . 10.1016/j.neuroscience.2011.03.061 . 38928854 .
  49. Andréen L, Nyberg S, Turkmen S, van Wingen G, Fernández G, Bäckström T . Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators . Psychoneuroendocrinology . 34 . 8 . 1121–1132 . September 2009 . 19272715 . 10.1016/j.psyneuen.2009.02.003 . 22259026 .
  50. Bäckström T, Bixo M, Johansson M, Nyberg S, Ossewaarde L, Ragagnin G, Savic I, Strömberg J, Timby E, van Broekhoven F, van Wingen G . 6 . Allopregnanolone and mood disorders . Progress in Neurobiology . 113 . 88–94 . February 2014 . 23978486 . 10.1016/j.pneurobio.2013.07.005 . 207407084 .
  51. Andréen L, Sundström-Poromaa I, Bixo M, Nyberg S, Bäckström T . Allopregnanolone concentration and mood--a bimodal association in postmenopausal women treated with oral progesterone . Psychopharmacology . 187 . 2 . 209–221 . August 2006 . 16724185 . 10.1007/s00213-006-0417-0 . 1933116 .
  52. Zorumski CF, Paul SM, Covey DF, Mennerick S . Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond . Neurobiology of Stress . 11 . 100196 . November 2019 . 31649968 . 6804800 . 10.1016/j.ynstr.2019.100196 .
  53. Warner MD, Peabody CA, Whiteford HA, Hollister LE . Alprazolam as an antidepressant . The Journal of Clinical Psychiatry . 49 . 4 . 148–150 . April 1988 . 3281931 .
  54. Srisurapanont M, Boonyanaruthee V . Alprazolam and standard antidepressants in the treatment of depression: a meta-analysis of the antidepressant effect . Journal of the Medical Association of Thailand = Chotmaihet Thangphaet . 80 . 3 . 183–188 . March 1997 . 9175386 . Centre for Reviews and Dissemination (UK) .
  55. Scott LJ . Brexanolone: First Global Approval . Drugs . 79 . 7 . 779–783 . May 2019 . 31006078 . 10.1007/s40265-019-01121-0 . 123095177 .
  56. Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A . Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis . Proceedings of the National Academy of Sciences of the United States of America . 103 . 39 . 14602–14607 . September 2006 . 16984997 . 1600006 . 10.1073/pnas.0606544103 . free . 2006PNAS..10314602A . doi .
  57. Web site: Drug Trials Snapshots: Zulresso . U.S. Food and Drug Administration (FDA) . 2 April 2019 . https://web.archive.org/web/20190928054122/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-zulresso . 28 September 2019 . live . 24 November 2019.
  58. Web site: INN Brexanolone . 3 September 2019 . 4 November 2021 . https://web.archive.org/web/20211104143210/https://extranet.who.int/soinn/?i=10446 . dead .
  59. Web site: KEGG DRUG: Brexanolone.
  60. Web site: Brexanolone - Sage Therapeutics. AdisInsight.
  61. Morrow AL, Boero G, Porcu P . A Rationale for Allopregnanolone Treatment of Alcohol Use Disorders: Basic and Clinical Studies . Alcoholism: Clinical and Experimental Research . 44 . 2 . 320–339 . February 2020 . 31782169 . 7018555 . 10.1111/acer.14253 .
  62. Andréen L, Spigset O, Andersson A, Nyberg S, Bäckström T . Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone . Maturitas . 54 . 3 . 238–244 . June 2006 . 16406399 . 10.1016/j.maturitas.2005.11.005 .
  63. Book: Devinsky O, Schachter S, Pacia S . Complementary and Alternative Therapies for Epilepsy . 1 January 2005 . Demos Medical Publishing . 978-1-934559-08-6 . 378–.
  64. Saudan C, Desmarchelier A, Sottas PE, Mangin P, Saugy M . Urinary marker of oral pregnenolone administration . Steroids . 70 . 3 . 179–183 . March 2005 . 15763596 . 10.1016/j.steroids.2004.12.007 . 25490229 .
  65. Piper T, Schlug C, Mareck U, Schänzer W . Investigations on changes in ¹³C/¹²C ratios of endogenous urinary steroids after pregnenolone administration . Drug Testing and Analysis . 3 . 5 . 283–290 . May 2011 . 21538944 . 10.1002/dta.281 .
  66. Sripada RK, Marx CE, King AP, Rampton JC, Ho SS, Liberzon I . Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits . Biological Psychiatry . 73 . 11 . 1045–1053 . June 2013 . 23348009 . 3648625 . 10.1016/j.biopsych.2012.12.008 .
  67. Ducharme N, Banks WA, Morley JE, Robinson SM, Niehoff ML, Mattern C, Farr SA . Brain distribution and behavioral effects of progesterone and pregnenolone after intranasal or intravenous administration . European Journal of Pharmacology . 641 . 2–3 . 128–134 . September 2010 . 20570588 . 3008321 . 10.1016/j.ejphar.2010.05.033 .
  68. He J, Evans CO, Hoffman SW, Oyesiku NM, Stein DG . Progesterone and allopregnanolone reduce inflammatory cytokines after traumatic brain injury . Experimental Neurology . 189 . 2 . 404–412 . October 2004 . 15380490 . 10.1016/j.expneurol.2004.06.008 . 10008079 .