Allopregnanolone

Brexanolone is used to treat postpartum depression in adult women, administered as a continuous intravenous infusion over a period of 60 hours, and essential tremor.{{cite web |title=Zulresso (brexanolone) dosing, indications, interactions, adverse effects, and more |url=https://reference.medscape.com/drug/zulresso-brexanolone-1000299 |access-date=2023-09-30 |website=reference.medscape.com}}

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.{{cite journal | vauthors = 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 | display-authors = 6 | title = Brexanolone, a GABA_A Modulator, in the Treatment of Postpartum Depression in Adults: A Comprehensive Review | journal = Frontiers in Psychiatry | volume = 12 | issue = | pages = 699740 | date = 2021 | pmid = 34594247 | pmc = 8477036 | doi = 10.3389/fpsyt.2021.699740 | doi-access = free }}

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%).{{cite journal | vauthors = Walkery A, Leader LD, Cooke E, VandenBerg A | title = Review of Allopregnanolone Agonist Therapy for the Treatment of Depressive Disorders | language = English | journal = Drug Design, Development and Therapy | volume = 15 | pages = 3017–3026 | date = 2021-07-09 | pmid = 34267503 | pmc = 8276990 | doi = 10.2147/DDDT.S240856 | doi-access = free }} 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.

Allopregnanolone possesses a wide variety of effects, including, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding,{{cite journal | vauthors = Rougé-Pont F, Mayo W, Marinelli M, Gingras M, Le Moal M, Piazza PV | title = The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens | journal = The European Journal of Neuroscience | volume = 16 | issue = 1 | pages = 169–173 | date = July 2002 | pmid = 12153544 | doi = 10.1046/j.1460-9568.2002.02084.x | s2cid = 9953445 }} prosocial,{{cite journal | vauthors = Frye CA | title = Neurosteroids' effects and mechanisms for social, cognitive, emotional, and physical functions | journal = Psychoneuroendocrinology | volume = 34 | issue = Suppl 1 | pages = S143–S161 | date = December 2009 | pmid = 19656632 | pmc = 2898141 | doi = 10.1016/j.psyneuen.2009.07.005 }} antiaggressive,{{cite journal | vauthors = Pinna G, Costa E, Guidotti A | title = Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 6 | pages = 2135–2140 | date = February 2005 | pmid = 15677716 | pmc = 548579 | doi = 10.1073/pnas.0409643102 | doi-access = free | bibcode = 2005PNAS..102.2135P | title-link = doi }} prosexual, sedative, pro-sleep,{{cite journal | vauthors = Terán-Pérez G, Arana-Lechuga Y, Esqueda-León E, Santana-Miranda R, Rojas-Zamorano JÁ, Velázquez Moctezuma J | title = Steroid hormones and sleep regulation | journal = Mini Reviews in Medicinal Chemistry | volume = 12 | issue = 11 | pages = 1040–1048 | date = October 2012 | pmid = 23092405 | doi = 10.2174/138955712802762167 }} cognitive, memory-impairment, analgesic,{{cite journal | vauthors = Patte-Mensah C, Meyer L, Taleb O, Mensah-Nyagan AG | title = Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain | journal = Progress in Neurobiology | volume = 113 | pages = 70–78 | date = February 2014 | pmid = 23948490 | doi = 10.1016/j.pneurobio.2013.07.004 | s2cid = 207407077 }} 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.{{cite journal | vauthors = 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 | display-authors = 6 | title = Pathogenesis in menstrual cycle-linked CNS disorders | journal = Annals of the New York Academy of Sciences | volume = 1007 | issue = 1 | pages = 42–53 | date = December 2003 | pmid = 14993039 | doi = 10.1196/annals.1286.005 | s2cid = 20995334 | bibcode = 2003NYASA1007...42B | doi-access = free }}{{cite journal | vauthors = Guille C, Spencer S, Cavus I, Epperson CN | title = The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: implications for diagnosis and treatment | journal = Epilepsy & Behavior | volume = 13 | issue = 1 | pages = 12–24 | date = July 2008 | pmid = 18346939 | pmc = 4112568 | doi = 10.1016/j.yebeh.2008.02.004 }}{{cite journal | vauthors = Finocchi C, Ferrari M | title = Female reproductive steroids and neuronal excitability | journal = Neurological Sciences | volume = 32 | issue = Suppl 1 | pages = S31–S35 | date = May 2011 | pmid = 21533709 | doi = 10.1007/s10072-011-0532-5 | s2cid = 8885335 }}

During pregnancy, allopregnanolone and pregnanolone are involved in sedation and anesthesia of the fetus.{{cite journal | vauthors = Mellor DJ, Diesch TJ, Gunn AJ, Bennet L | title = The importance of 'awareness' for understanding fetal pain | journal = Brain Research. Brain Research Reviews | volume = 49 | issue = 3 | pages = 455–471 | date = November 2005 | pmid = 16269314 | doi = 10.1016/j.brainresrev.2005.01.006 | s2cid = 9833426 }}{{cite journal | vauthors = Lagercrantz H, Changeux JP | title = The emergence of human consciousness: from fetal to neonatal life | journal = Pediatric Research | volume = 65 | issue = 3 | pages = 255–260 | date = March 2009 | pmid = 19092726 | doi = 10.1203/PDR.0b013e3181973b0d | quote = [...] 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). | s2cid = 39391626 | doi-access = free | title-link = doi }}

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.{{cite journal|doi=10.15347/WJM/2023.003 |doi-access=free |title=Alternative androgen pathways |year=2023 | vauthors = Masiutin M, Yadav M |journal=WikiJournal of Medicine |volume=10 |pages=X |s2cid=257943362}}

Allopregnanolone is an endogenous inhibitory pregnane neurosteroid. It is made from pregnenolone, and is a positive allosteric modulator of the action of γ-aminobutyric acid (GABA) at GABA_A receptor. Allopregnanolone has effects similar to those of other positive allosteric modulators of the GABA action at GABA_A receptor such as the benzodiazepines, including anxiolytic, sedative, and anticonvulsant activity.{{cite journal | vauthors = Reddy DS, Rogawski MA, Rogawski MA, Olsen RW, Delgado-Escueta AV, Reddy DS, Rogawski MA | title = Neurosteroids — Endogenous Regulators of Seizure Susceptibility and Role in the Treatment of Epilepsy | journal = Jasper's Basic Mechanisms of the Epilepsies, 4th Edition | pages = 984–1002 | year = 2012 | pmid = 22787590 | doi = 10.1093/med/9780199746545.003.0077 | isbn = 9780199746545 }}{{cite journal | vauthors = Kokate TG, Svensson BE, Rogawski MA | title = Anticonvulsant activity of neurosteroids: correlation with gamma-aminobutyric acid-evoked chloride current potentiation | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 270 | issue = 3 | pages = 1223–1229 | date = September 1994 | pmid = 7932175 }} Endogenously produced allopregnanolone exerts a neurophysiological role by fine-tuning of GABA_A receptor and modulating the action of several positive allosteric modulators and agonists at GABA_A receptor.{{cite journal | vauthors = Pinna G, Uzunova V, Matsumoto K, Puia G, Mienville JM, Costa E, Guidotti A | title = Brain allopregnanolone regulates the potency of the GABA(A) receptor agonist muscimol | journal = Neuropharmacology | volume = 39 | issue = 3 | pages = 440–448 | date = January 2000 | pmid = 10698010 | doi = 10.1016/S0028-3908(99)00149-5 | s2cid = 42753647 }}

Allopregnanolone acts as a highly potent positive allosteric modulator of the GABA_A receptor. While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABA_A receptor isoforms, those isoforms containing δ subunits exhibit the greatest potentiation.{{cite journal | vauthors = Nik AM, Pressly B, Singh V, Antrobus S, Hulsizer S, Rogawski MA, Wulff H, Pessah IN | display-authors = 6 | title = Rapid Throughput Analysis of GABA_A Receptor Subtype Modulators and Blockers Using DiSBAC₁(3) Membrane Potential Red Dye | journal = Molecular Pharmacology | volume = 92 | issue = 1 | pages = 88–99 | date = July 2017 | pmid = 28428226 | pmc = 5452057 | doi = 10.1124/mol.117.108563 }} Allopregnanolone has also been found to act as a positive allosteric modulator of the GABA_A-ρ receptor, though the implications of this action are unclear.{{cite journal | vauthors = Morris KD, Moorefield CN, Amin J | title = Differential modulation of the gamma-aminobutyric acid type C receptor by neuroactive steroids | journal = Molecular Pharmacology | volume = 56 | issue = 4 | pages = 752–759 | date = October 1999 | pmid = 10496958 }}{{cite journal | vauthors = Li W, Jin X, Covey DF, Steinbach JH | title = Neuroactive steroids and human recombinant rho1 GABAC receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 323 | issue = 1 | pages = 236–247 | date = October 2007 | pmid = 17636008 | pmc = 3905684 | doi = 10.1124/jpet.107.127365 | s2cid = 12294587 }} In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be a negative allosteric modulator of nACh receptors,{{cite journal | vauthors = Bullock AE, Clark AL, Grady SR, Robinson SF, Slobe BS, Marks MJ, Collins AC | title = Neurosteroids modulate nicotinic receptor function in mouse striatal and thalamic synaptosomes | journal = Journal of Neurochemistry | volume = 68 | issue = 6 | pages = 2412–2423 | date = June 1997 | pmid = 9166735 | doi = 10.1046/j.1471-4159.1997.68062412.x | s2cid = 26195479 }} and also appears to act as a negative allosteric modulator of the 5-HT₃ receptor.{{cite journal | vauthors = Wetzel CH, Hermann B, Behl C, Pestel E, Rammes G, Zieglgänsberger W, Holsboer F, Rupprecht R | display-authors = 6 | title = Functional antagonism of gonadal steroids at the 5-hydroxytryptamine type 3 receptor | journal = Molecular Endocrinology | volume = 12 | issue = 9 | pages = 1441–1451 | date = September 1998 | pmid = 9731711 | doi = 10.1210/mend.12.9.0163 | doi-access = free | title-link = doi }} 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.{{cite journal | vauthors = Mellon SH | title = Neurosteroid regulation of central nervous system development | journal = Pharmacology & Therapeutics | volume = 116 | issue = 1 | pages = 107–124 | date = October 2007 | pmid = 17651807 | pmc = 2386997 | doi = 10.1016/j.pharmthera.2007.04.011 }}

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.{{cite journal | vauthors = Rupprecht R, Reul JM, Trapp T, van Steensel B, Wetzel C, Damm K, Zieglgänsberger W, Holsboer F | display-authors = 6 | title = Progesterone receptor-mediated effects of neuroactive steroids | journal = Neuron | volume = 11 | issue = 3 | pages = 523–530 | date = September 1993 | pmid = 8398145 | doi = 10.1016/0896-6273(93)90156-l | s2cid = 11205767 }}{{cite journal | vauthors = Reddy DS, Estes WA | title = Clinical Potential of Neurosteroids for CNS Disorders | journal = Trends in Pharmacological Sciences | volume = 37 | issue = 7 | pages = 543–561 | date = July 2016 | pmid = 27156439 | pmc = 5310676 | doi = 10.1016/j.tips.2016.04.003 }} (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 GABA_A receptor.{{cite journal | vauthors = Thomas P, Pang Y | title = Membrane progesterone receptors: evidence for neuroprotective, neurosteroid signaling and neuroendocrine functions in neuronal cells | journal = Neuroendocrinology | volume = 96 | issue = 2 | pages = 162–171 | year = 2012 | pmid = 22687885 | pmc = 3489003 | doi = 10.1159/000339822 }}{{cite journal | vauthors = Pang Y, Dong J, Thomas P | title = Characterization, neurosteroid binding and brain distribution of human membrane progesterone receptors δ and {epsilon} (mPRδ and mPR{epsilon}) and mPRδ involvement in neurosteroid inhibition of apoptosis | journal = Endocrinology | volume = 154 | issue = 1 | pages = 283–295 | date = January 2013 | pmid = 23161870 | pmc = 3529379 | doi = 10.1210/en.2012-1772 }} The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective and antigonadotropic properties.{{cite journal | vauthors = Sleiter N, Pang Y, Park C, Horton TH, Dong J, Thomas P, Levine JE | title = Progesterone receptor A (PRA) and PRB-independent effects of progesterone on gonadotropin-releasing hormone release | journal = Endocrinology | volume = 150 | issue = 8 | pages = 3833–3844 | date = August 2009 | pmid = 19423765 | pmc = 2717864 | doi = 10.1210/en.2008-0774 }} Also like progesterone, recent evidence has shown that allopregnanolone is an activator of the pregnane X receptor.{{cite journal | vauthors = Lamba V, Yasuda K, Lamba JK, Assem M, Davila J, Strom S, Schuetz EG | title = PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators | journal = Toxicology and Applied Pharmacology | volume = 199 | issue = 3 | pages = 251–265 | date = September 2004 | pmid = 15364541 | doi = 10.1016/j.taap.2003.12.027 | bibcode = 2004ToxAP.199..251L }}

Similarly to many other GABA_A receptor positive allosteric modulators, allopregnanolone has been found to act as an inhibitor of L-type voltage-gated calcium channels (L-VGCCs),{{cite journal | vauthors = Hu AQ, Wang ZM, Lan DM, Fu YM, Zhu YH, Dong Y, Zheng P | title = Inhibition of evoked glutamate release by neurosteroid allopregnanolone via inhibition of L-type calcium channels in rat medial prefrontal cortex | journal = Neuropsychopharmacology | volume = 32 | issue = 7 | pages = 1477–1489 | date = July 2007 | pmid = 17151597 | doi = 10.1038/sj.npp.1301261 | doi-access = free | title-link = doi }} including α₁ subtypes Ca_v1.2 and Ca_v1.3.{{cite journal | vauthors = Earl DE, Tietz EI | title = Inhibition of recombinant L-type voltage-gated calcium channels by positive allosteric modulators of GABAA receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 337 | issue = 1 | pages = 301–311 | date = April 2011 | pmid = 21262851 | pmc = 3063747 | doi = 10.1124/jpet.110.178244 }} 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).{{cite journal | vauthors = Keitel V, Görg B, Bidmon HJ, Zemtsova I, Spomer L, Zilles K, Häussinger D | title = The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain | journal = Glia | volume = 58 | issue = 15 | pages = 1794–1805 | date = November 2010 | pmid = 20665558 | doi = 10.1002/glia.21049 | s2cid = 37368754 }} 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.

Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety, irritability, and aggression.{{cite journal | vauthors = Bäckström T, Haage D, Löfgren M, Johansson IM, Strömberg J, Nyberg S, Andréen L, Ossewaarde L, van Wingen GA, Turkmen S, Bengtsson SK | display-authors = 6 | title = Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons | journal = Neuroscience | volume = 191 | pages = 46–54 | date = September 2011 | pmid = 21600269 | doi = 10.1016/j.neuroscience.2011.03.061 | s2cid = 38928854 }}{{cite journal | vauthors = Andréen L, Nyberg S, Turkmen S, van Wingen G, Fernández G, Bäckström T | title = Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators | journal = Psychoneuroendocrinology | volume = 34 | issue = 8 | pages = 1121–1132 | date = September 2009 | pmid = 19272715 | doi = 10.1016/j.psyneuen.2009.02.003 | s2cid = 22259026 }}{{cite journal | vauthors = Bäckström T, Bixo M, Johansson M, Nyberg S, Ossewaarde L, Ragagnin G, Savic I, Strömberg J, Timby E, van Broekhoven F, van Wingen G | display-authors = 6 | title = Allopregnanolone and mood disorders | journal = Progress in Neurobiology | volume = 113 | pages = 88–94 | date = February 2014 | pmid = 23978486 | doi = 10.1016/j.pneurobio.2013.07.005 | s2cid = 207407084 }} This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABA_A 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 GABA_A 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.{{cite journal | vauthors = Andréen L, Sundström-Poromaa I, Bixo M, Nyberg S, Bäckström T | title = Allopregnanolone concentration and mood--a bimodal association in postmenopausal women treated with oral progesterone | journal = Psychopharmacology | volume = 187 | issue = 2 | pages = 209–221 | date = August 2006 | pmid = 16724185 | doi = 10.1007/s00213-006-0417-0 | s2cid = 1933116 }}

The mechanism by which neurosteroid GABA_A receptor PAMs like brexanolone have antidepressant effects is unknown.{{cite journal | vauthors = Zorumski CF, Paul SM, Covey DF, Mennerick S | title = Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond | journal = Neurobiology of Stress | volume = 11 | pages = 100196 | date = November 2019 | pmid = 31649968 | pmc = 6804800 | doi = 10.1016/j.ynstr.2019.100196 }} Other GABA_A receptor PAMs, such as benzodiazepines, are not thought of as antidepressants and have no proven efficacy, although alprazolam has historically been prescribed for depression.{{cite journal | vauthors = Warner MD, Peabody CA, Whiteford HA, Hollister LE | title = Alprazolam as an antidepressant | journal = The Journal of Clinical Psychiatry | volume = 49 | issue = 4 | pages = 148–150 | date = April 1988 | pmid = 3281931 }}{{cite journal | vauthors = Srisurapanont M, Boonyanaruthee V | title = Alprazolam and standard antidepressants in the treatment of depression: a meta-analysis of the antidepressant effect | journal = Journal of the Medical Association of Thailand = Chotmaihet Thangphaet | volume = 80 | issue = 3 | pages = 183–188 | date = March 1997 | pmid = 9175386 | url = https://www.ncbi.nlm.nih.gov/books/NBK67062/ | publisher = Centre for Reviews and Dissemination (UK) }} Neurosteroid GABA_A receptor PAMs are known to interact with GABA_A receptors and subpopulations differently than benzodiazepines. GABA_A receptor-potentiating neurosteroids may preferentially target δ-subunit–containing GABA_A receptors, and enhance both tonic and phasic inhibition mediated by GABA_A 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.

Brexanolone has low oral bioavailability of less than 5%, necessitating non-oral administration.{{cite journal | vauthors = Scott LJ | title = Brexanolone: First Global Approval | journal = Drugs | volume = 79 | issue = 7 | pages = 779–783 | date = May 2019 | pmid = 31006078 | doi = 10.1007/s40265-019-01121-0 | s2cid = 123095177 }} 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.

{{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, 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).

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.{{cite journal | vauthors = Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A | title = Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 39 | pages = 14602–14607 | date = September 2006 | pmid = 16984997 | pmc = 1600006 | doi = 10.1073/pnas.0606544103 | doi-access = free | bibcode = 2006PNAS..10314602A | title-link = doi }}

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.

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.{{cite web | title=Drug Trials Snapshots: Zulresso | website=U.S. Food and Drug Administration (FDA) | date=2 April 2019 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-zulresso | archive-url=https://web.archive.org/web/20190928054122/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-zulresso | archive-date=28 September 2019 | url-status=live | access-date=24 November 2019}}

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

Brexanolone is both the International Nonproprietary Name and the United States Adopted Name in the context of its use as a medication.{{cite web |title=INN Brexanolone |url=https://mednet-communities.net/inn/db/ViewINN.aspx?i=10446 |access-date=3 September 2019 |archive-date=4 November 2021 |archive-url=https://web.archive.org/web/20211104143210/https://extranet.who.int/soinn/?i=10446 |url-status=dead }}{{cite web | url=https://www.genome.jp/dbget-bin/www_bget?dr:D11149 |title = KEGG DRUG: Brexanolone}}

Zulresso is a brand name of the medication.

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

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).

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.{{cite web|title=Brexanolone - Sage Therapeutics|url=http://adisinsight.springer.com/drugs/800039944|publisher=AdisInsight}}

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.{{cite journal | vauthors = Morrow AL, Boero G, Porcu P | title = A Rationale for Allopregnanolone Treatment of Alcohol Use Disorders: Basic and Clinical Studies | journal = Alcoholism: Clinical and Experimental Research | volume = 44 | issue = 2 | pages = 320–339 | date = February 2020 | pmid = 31782169 | pmc = 7018555 | doi = 10.1111/acer.14253 }}

Exogenous progesterone, such as oral progesterone, elevates allopregnanolone levels in the body with good dose-to-serum level correlations.{{cite journal | vauthors = Andréen L, Spigset O, Andersson A, Nyberg S, Bäckström T | title = Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone | journal = Maturitas | volume = 54 | issue = 3 | pages = 238–244 | date = June 2006 | pmid = 16406399 | doi = 10.1016/j.maturitas.2005.11.005 }} 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,{{cite book | vauthors = Devinsky O, Schachter S, Pacia S | title = Complementary and Alternative Therapies for Epilepsy | url = https://books.google.com/books?id=WVUE-6Xdny4C&pg=PT378 | date = 1 January 2005 | publisher = Demos Medical Publishing | isbn = 978-1-934559-08-6 | pages = 378–}} 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,{{cite journal | vauthors = Saudan C, Desmarchelier A, Sottas PE, Mangin P, Saugy M | title = Urinary marker of oral pregnenolone administration | journal = Steroids | volume = 70 | issue = 3 | pages = 179–183 | date = March 2005 | pmid = 15763596 | doi = 10.1016/j.steroids.2004.12.007 | s2cid = 25490229 }}{{cite journal | vauthors = Piper T, Schlug C, Mareck U, Schänzer W | title = Investigations on changes in ¹³C/¹²C ratios of endogenous urinary steroids after pregnenolone administration | journal = Drug Testing and Analysis | volume = 3 | issue = 5 | pages = 283–290 | date = May 2011 | pmid = 21538944 | doi = 10.1002/dta.281 }}{{cite journal | vauthors = Sripada RK, Marx CE, King AP, Rampton JC, Ho SS, Liberzon I | title = Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits | journal = Biological Psychiatry | volume = 73 | issue = 11 | pages = 1045–1053 | date = June 2013 | pmid = 23348009 | pmc = 3648625 | doi = 10.1016/j.biopsych.2012.12.008 }} though also of pregnenolone sulfate.{{cite journal | vauthors = Ducharme N, Banks WA, Morley JE, Robinson SM, Niehoff ML, Mattern C, Farr SA | title = Brain distribution and behavioral effects of progesterone and pregnenolone after intranasal or intravenous administration | journal = European Journal of Pharmacology | volume = 641 | issue = 2–3 | pages = 128–134 | date = September 2010 | pmid = 20570588 | pmc = 3008321 | doi = 10.1016/j.ejphar.2010.05.033 }}

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.{{cite journal | vauthors = He J, Evans CO, Hoffman SW, Oyesiku NM, Stein DG | title = Progesterone and allopregnanolone reduce inflammatory cytokines after traumatic brain injury | journal = Experimental Neurology | volume = 189 | issue = 2 | pages = 404–412 | date = October 2004 | pmid = 15380490 | doi = 10.1016/j.expneurol.2004.06.008 | s2cid = 10008079 }}

• Brexanolone caprilcerbate

{{Reflist}}

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• {{cite journal | vauthors = Herd MB, Belelli D, Lambert JJ | title = Neurosteroid modulation of synaptic and extrasynaptic GABA(A) receptors | journal = Pharmacology & Therapeutics | volume = 116 | issue = 1 | pages = 20–34 | date = October 2007 | pmid = 17531325 | doi = 10.1016/j.pharmthera.2007.03.007 | arxiv = 1607.02870 }}
• {{cite journal | vauthors = Zorumski CF, Paul SM, Covey DF, Mennerick S | title = Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond | journal = Neurobiology of Stress | volume = 11 | pages = 100196 | date = November 2019 | pmid = 31649968 | pmc = 6804800 | doi = 10.1016/j.ynstr.2019.100196 }}

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• {{ClinicalTrialsGov|NCT02942004|A Study to Evaluate Efficacy and Safety of SAGE-547 in Participants With Severe Postpartum Depression (547-PPD-202B)}}
• {{ClinicalTrialsGov|NCT02614547|A Study to Evaluate SAGE-547 in Patients With Severe Postpartum Depression}}
• {{ClinicalTrialsGov|NCT02942017|A Study to Evaluate Safety and Efficacy of SAGE-547 in Participants With Moderate Postpartum Depression (547-PPD-202C)}}

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