Neuroactive steroids, also known as neurosteroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term neurosteroid was coined by the French physiologist Étienne-Émile Baulieu and refers to steroids synthesized in the brain. The term , neuroactive steroid refers to steroids that can be synthesized in brain or are synthesized by an endocrine gland that then reach the brain through the bloodstream and have effects on brain function. The term neuroactive steroids was first coined in 1992 by Steven Paul and Robert Purdy . In addition to their actions on neuronal membrane receptors, some of these steroids may also exert effects on gene expression via nuclear steroid hormone receptors. Neurosteroids have a wide range of potential clinical applications from sedation to treatment of epilepsy and traumatic brain injury. Ganaxolone, a synthetic analog of the endogenous neurosteroid allopregnanolone, is under investigation for the treatment of epilepsy.
- 1 Classifications and mechanisms
- 2 Biosynthesis
- 3 Function
- 4 Therapeutic application
- 5 Role in antidepressant action
- 6 Benzodiazepine effects on neurosteroids
- 7 See also
- 8 References
- 9 Further reading
Classifications and mechanisms
These neurosteroids exert inhibitory actions on neurotransmission. They act as positive allosteric modulators of the GABAA receptor (especially δ subunit-containing isoforms), and possess, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding, prosocial, antiaggressive, prosexual, sedative, pro-sleep, cognitive and memory-impairing, analgesic, anesthetic, anticonvulsant, neuroprotective, and neurogenic effects.
- 5α-Dihydroprogesterone (5α-DHP)
- 5β-Dihydroprogesterone (5β-DHP)
- 3α-Dihydroprogesterone (3α-DHP)
- Allopregnanolone (3α,5α-THP)
- Pregnanolone (3α,5β-THP)
- Dihydrodeoxycorticosterone (DHDOC)
- Tetrahydrodeoxycorticosterone (THDOC)
These neurosteroids have excitatory effects on neurotransmission. They act as potent negative allosteric modulators of the GABAA receptor, weak positive allosteric modulators of the NMDA receptor, and/or agonists of the σ1 receptor, and mostly have antidepressant, anxiogenic, cognitive and memory-enhancing, convulsant, neuroprotective, and neurogenic effects.
Certain other endogenous steroids, such as pregnenolone, progesterone, estradiol, and corticosterone are also neurosteroids. However, unlike those listed above, these neurosteroids do not modulate the GABAA or NMDA receptors, and instead affect various other cell surface receptors and non-genomic targets. Also, many endogenous steroids, including pregnenolone, progesterone, corticosterone, deoxycorticosterone, DHEA, and testosterone, are metabolized into (other) neurosteroids, effectively functioning as so-called proneurosteroids.
Neurosteroids are synthesized from cholesterol, which is converted into pregnenolone and then into all other endogenous steroids. Neurosteroids are produced in the brain after local synthesis or by conversion of peripherally-derived adrenal steroids or gonadal steroids. They accumulate especially in myelinating glial cells, from cholesterol or steroidal precursors imported from peripheral sources. 5α-reductase type I and 3α-hydroxysteroid dehydrogenase are involved in the biosynthesis of inhibitory neurosteroids, while 3β-hydroxysteroid dehydrogenase and hydroxysteroid sulfotransferases are involved in excitatory neurosteroid production.
Some major known biological functions of neurosteroids include modulation of neural plasticity, learning and memory processes, behavior, and seizure susceptibility, as well as responses to stress, anxiety, and depression. Neurosteroids also appear to play an important role in various sexually-dimorphic behaviors and emotional responses.
Acute stress elevates the levels of inhibitory neurosteroids like allopregnanolone, and these neurosteroids are known to counteract many of the effects of stress. This is similar to the case of endorphins, which are released in response to stress and physical pain and counteract the negative subjective effects of such states. As such, it has been suggested that one of the biological functions of these neuromodulators may be to help maintain emotional homeostasis. Interestingly, chronic stress has been associated with diminished levels of allopregnanolone and altered allopregnanolone stress responsivity, psychiatric disorders, and hypothalamic-pituitary-adrenal axis dysregulation.
It is thought that fluctuations in the levels of inhibitory neurosteroids during the menstrual cycle and pregnancy play an important role in a variety of women's conditions, including premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), postpartum depression (PPD), postpartum psychosis, and catamenial epilepsy. In addition, it is thought that changes in neurosteroid levels may be involved in the changes in mood, anxiety, and sexual desire that occur during puberty in both sexes and during menopause in women.
Elevated levels of inhibitory neurosteroids, namely allopregnanolone, can produce paradoxical effects, such as negative mood, anxiety, irritability, and aggression. This appears to be because these neurosteroids, like other positive allosteric modulators of the GABAA receptor such as the benzodiazepines, barbiturates, and ethanol, possess biphasic, U-shaped actions – moderate levels (in the range of 1.5–2 nM/L total alloprogesterone, which are approximately equivalent to luteal phase levels) inhibit the activity of the GABAA receptor, while lower and higher concentrations facilitate the activity of the receptor.
Several synthetic neurosteroids have been used as sedatives for the purpose of general anaesthesia for carrying out surgical procedures. The best known of these are alphaxolone, alphadolone, hydroxydione and minaxolone. The first of these to be introduced was hydroxydione, which is the esterified 21-hydroxy derivative of 5β-pregnanedione. Hydroxydione proved to be a useful anaesthetic drug with a good safety profile, but was painful and irritating when injected probably due to poor water solubility. This led to the development of newer neuroactive steroids. The next drug from this family to be marketed was a mixture of alphaxolone and alphadolone, known as Althesin. This was withdrawn from human use due to rare but serious toxic reactions, but is still used in veterinary medicine. The next neurosteroid anaesthetic introduced into human medicine was the newer drug minaxolone, which is around three times more potent than althesin and retains the favourable safety profile, without the toxicity problems seen with althesin. However this drug was also ultimately withdrawn, not because of problems in clinical use, but because animal studies suggested potential carcinogenicity and since alternative agents were available it was felt that the possible risk outweighed the benefit of keeping the drug on the market.
The neurosteroid ganaxolone, an analog of the progesterone metabolite allopregnanolone, has been extensively investigated in animal models and is currently in clinical trials for the treatment of epilepsy. Neurosteroids, including ganaxolone have a broad spectrum of activity in animal models. They may have advantages over other GABAA receptor modulators, notably benzodiazepines, in that tolerance does not appear to occur with extended use.
A randomized, placebo controlled, 10 week phase 2 clinical trial of orally administered ganaxolone in adults with partial onset seizure demonstrated that the treatment is safe, well tolerated and efficacious. The drug continued to demonstrate efficacy in an 104 week open label extension. Data from non-clinical studies suggest that ganaxolone may have low risk for use in pregnancy. In addition to use in the treatment of epilepsy, the drug has potential in the treatment of a broad range of neurological and psychiatric conditions. Proof-of-concept studies are currently underway in posttraumatic stress disorder and fragile X syndrome.
Researchers have suggested the use of so-called "neurosteroid replacement therapy" as a way of treating catamenial epilepsy with neuroactive steroids such as ganaxolone during the period of the menstrual cycle when seizure frequency increases. Micronized progesterone, which behaves reliably as a prodrug to allopregnanolone, has been suggested as a treatment for catamenial epilepsy in the same manner.
Role in antidepressant action
Certain antidepressant drugs such as fluoxetine and fluvoxamine, which are generally thought to affect depression by acting as selective serotonin reuptake inhibitors (SSRIs), have also been found to normalize the levels of certain neurosteroids (which are frequently deficient in depressed patients) at doses that are inactive in affecting the reuptake of serotonin. This suggests that other actions involving neurosteroids may also be at play in the effectiveness of these drugs against depression.
Benzodiazepine effects on neurosteroids
Benzodiazepines may influence neurosteroid metabolism by virtue of their actions on translocator protein (TSPO; "peripheral benzodiazepine receptor"). The pharmacological actions of benzodiazepines at the GABAA receptor are similar to those of neurosteroids. Factors which affect the ability of individual benzodiazepines to alter neurosteroid levels may depend upon whether the individual benzodiazepine drug interacts with TSPO. Some benzodiazepines may also inhibit neurosteroidogenic enzymes reducing neurosteroid synthesis.
- Paul SM, Purdy RH (Mar 1992). "Neuroactive steroids" (abstract). FASEB Journal 6 (6): 2311–22. PMID 1347506.
- Lan NC, Gee KW (Dec 1994). "Neuroactive steroid actions at the GABAA receptor". Hormones and Behavior 28 (4): 537–44. doi:10.1006/hbeh.1994.1052. PMID 7729823.
- Reddy DS (2010). "Neurosteroids: endogenous role in the human brain and therapeutic potentials". Progress in Brain Research 186: 113–37. doi:10.1016/B978-0-444-53630-3.00008-7. PMC 3139029. PMID 21094889.
- Reddy DS, Rogawski MA (2012). "Neurosteroids — Endogenous Regulators of Seizure Susceptibility and Role in the Treatment of Epilepsy". In Noebels JL, Avoli M, Rogawski MA et al. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US).
- Srivastava DP, Waters EM, Mermelstein PG, Kramár EA, Shors TJ, Liu F (Nov 2011). "Rapid estrogen signaling in the brain: implications for the fine-tuning of neuronal circuitry". The Journal of Neuroscience 31 (45): 16056–63. doi:10.1523/JNEUROSCI.4097-11.2011. PMC 3245715. PMID 22072656.
- Reddy DS, Rogawski MA (Apr 2009). "Neurosteroid replacement therapy for catamenial epilepsy". Neurotherapeutics 6 (2): 392–401. doi:10.1016/j.nurt.2009.01.006. PMC 2682439. PMID 19332335.
- Morrow AL (Oct 2007). "Recent developments in the significance and therapeutic relevance of neuroactive steroids--Introduction to the special issue". Pharmacology & Therapeutics 116 (1): 1–6. doi:10.1016/j.pharmthera.2007.04.003. PMC 2047816. PMID 17531324.
- Dubrovsky BO (Feb 2005). "Steroids, neuroactive steroids and neurosteroids in psychopathology". Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2): 169–92. doi:10.1016/j.pnpbp.2004.11.001. PMID 15694225.
- Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS (Jan 2013). "Progress report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI)". Epilepsy Research 103 (1): 2–30. doi:10.1016/j.eplepsyres.2012.10.001. PMID 23219031.
- Rougé-Pont F, Mayo W, Marinelli M, Gingras M, Le Moal M, Piazza PV (Jul 2002). "The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens". The European Journal of Neuroscience 16 (1): 169–73. doi:10.1046/j.1460-9568.2002.02084.x. PMID 12153544.
- Frye CA (Dec 2009). "Neurosteroids' effects and mechanisms for social, cognitive, emotional, and physical functions". Psychoneuroendocrinology. 34 Suppl 1: S143–61. doi:10.1016/j.psyneuen.2009.07.005. PMC 2898141. PMID 19656632.
- Pinna G, Costa E, Guidotti A (Feb 2005). "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): 2135–40. doi:10.1073/pnas.0409643102. PMC 548579. PMID 15677716.
- Terán-Pérez G, Arana-Lechuga Y, Esqueda-León E, Santana-Miranda R, Rojas-Zamorano JÁ, Velázquez Moctezuma J (Oct 2012). "Steroid hormones and sleep regulation". Mini Reviews in Medicinal Chemistry 12 (11): 1040–8. doi:10.2174/138955712802762167. PMID 23092405.
- Patte-Mensah C, Meyer L, Taleb O, Mensah-Nyagan AG (Feb 2014). "Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain". Progress in Neurobiology 113: 70–8. doi:10.1016/j.pneurobio.2013.07.004. PMID 23948490.
- Hénin J, Salari R, Murlidaran S, Brannigan G (2014). "A predicted binding site for cholesterol on the GABAA receptor". Biophys. J. 106 (9): 1938–49. doi:10.1016/j.bpj.2014.03.024. PMID 24806926.
- Christopher H. Hawkes, Richard L. Doty (12 February 2009). The Neurology of Olfaction. Cambridge University Press. pp. 37–. ISBN 978-0-521-68216-9.
- Monti-Bloch L, Jennings-White C, Dolberg DS, Berliner DL (1994). "The human vomeronasal system". Psychoneuroendocrinology 19 (5-7): 673–86. doi:10.1016/0306-4530(94)90049-3. PMID 7938363.
- Liebowitz MR, Salman E, Nicolini H, Rosenthal N, Hanover R, Monti L (Jun 2014). "Effect of an acute intranasal aerosol dose of PH94B on social and performance anxiety in women with social anxiety disorder" (PDF). The American Journal of Psychiatry 171 (6): 675–82. doi:10.1176/appi.ajp.2014.12101342. PMID 24700254.
- Marx CE, Bradford DW, Hamer RM, Naylor JC, Allen TB, Lieberman JA, Strauss JL, Kilts JD (Sep 2011). "Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence". Neuroscience 191: 78–90. doi:10.1016/j.neuroscience.2011.06.076. PMID 21756978.
- Baulieu E, Schumacher M (2000). "Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination". Steroids 65 (10-11): 605–12. doi:10.1016/s0039-128x(00)00173-2. PMID 11108866.
- Thomas P, Pang Y (2012). "Membrane progesterone receptors: evidence for neuroprotective, neurosteroid signaling and neuroendocrine functions in neuronal cells". Neuroendocrinology 96 (2): 162–71. doi:10.1159/000339822. PMC 3489003. PMID 22687885.
- Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A (Sep 2006). "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): 14602–7. doi:10.1073/pnas.0606544103. PMC 1600006. PMID 16984997.
- Mellon SH, Griffin LD (2002). "Neurosteroids: biochemistry and clinical significance". Trends in Endocrinology and Metabolism 13 (1): 35–43. doi:10.1016/S1043-2760(01)00503-3. PMID 11750861.
- Benarroch EE (Mar 2007). "Neurosteroids: endogenous modulators of neuronal excitability and plasticity". Neurology 68 (12): 945–7. doi:10.1212/01.wnl.0000257836.09570.e1. PMID 17372131.
- Vallée M, Mayo W, Koob GF, Le Moal M (2001). "Neurosteroids in learning and memory processes". International Review of Neurobiology 46: 273–320. doi:10.1016/s0074-7742(01)46066-1. PMID 11599303.
- Engel SR, Grant KA (2001). "Neurosteroids and behavior". International Review of Neurobiology 46: 321–48. PMID 11599304.
- King SR (2008). "Emerging roles for neurosteroids in sexual behavior and function". Journal of Andrology 29 (5): 524–33. doi:10.2164/jandrol.108.005660. PMID 18567641.
- Joshi S, Rajasekaran K, Kapur J (Jun 2013). "GABAergic transmission in temporal lobe epilepsy: the role of neurosteroids". Experimental Neurology 244: 36–42. doi:10.1016/j.expneurol.2011.10.028. PMC 3319002. PMID 22101060.
- Girdler SS, Klatzkin R (Oct 2007). "Neurosteroids in the context of stress: implications for depressive disorders". Pharmacology & Therapeutics 116 (1): 125–39. doi:10.1016/j.pharmthera.2007.05.006. PMC 2650267. PMID 17597217.
- Bali A, Jaggi AS (Jan 2014). "Multifunctional aspects of allopregnanolone in stress and related disorders". Progress in Neuro-Psychopharmacology & Biological Psychiatry 48: 64–78. doi:10.1016/j.pnpbp.2013.09.005. PMID 24044974.
- Gunn BG, Cunningham L, Mitchell SG, Swinny JD, Lambert JJ, Belelli D (Jan 2015). "GABAA receptor-acting neurosteroids: a role in the development and regulation of the stress response". Frontiers in Neuroendocrinology 36: 28–48. doi:10.1016/j.yfrne.2014.06.001. PMID 24929099.
- 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 (Dec 2003). "Pathogenesis in menstrual cycle-linked CNS disorders". Annals of the New York Academy of Sciences 1007: 42–53. doi:10.1196/annals.1286.005. PMID 14993039.
- Guille C, Spencer S, Cavus I, Epperson CN (Jul 2008). "The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: implications for diagnosis and treatment". Epilepsy & Behavior 13 (1): 12–24. doi:10.1016/j.yebeh.2008.02.004. PMC 4112568. PMID 18346939.
- Finocchi C, Ferrari M (May 2011). "Female reproductive steroids and neuronal excitability". Neurological Sciences. 32 Suppl 1: S31–5. doi:10.1007/s10072-011-0532-5. PMID 21533709.
- Genazzani AR, Bernardi F, Monteleone P, Luisi S, Luisi M (2000). "Neuropeptides, neurotransmitters, neurosteroids, and the onset of puberty". Annals of the New York Academy of Sciences 900: 1–9. doi:10.1111/j.1749-6632.2000.tb06210.x. PMID 10818386.
- Melcangi RC, Panzica G, Garcia-Segura LM (Sep 2011). "Neuroactive steroids: focus on human brain". Neuroscience 191: 1–5. doi:10.1016/j.neuroscience.2011.06.024. PMID 21704130.
- Andréen L, Sundström-Poromaa I, Bixo M, Nyberg S, Bäckström T (Aug 2006). "Allopregnanolone concentration and mood--a bimodal association in postmenopausal women treated with oral progesterone". Psychopharmacology 187 (2): 209–21. doi:10.1007/s00213-006-0417-0. PMID 16724185.
- Bäckström T, Haage D, Löfgren M, Johansson IM, Strömberg J, Nyberg S, Andréen L, Ossewaarde L, van Wingen GA, Turkmen S, Bengtsson SK (Sep 2011). "Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons". Neuroscience 191: 46–54. doi:10.1016/j.neuroscience.2011.03.061. PMID 21600269.
- Andréen L, Nyberg S, Turkmen S, van Wingen G, Fernández G, Bäckström T (Sep 2009). "Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators". Psychoneuroendocrinology 34 (8): 1121–32. doi:10.1016/j.psyneuen.2009.02.003. PMID 19272715.
- Bäckström T, Bixo M, Johansson M, Nyberg S, Ossewaarde L, Ragagnin G, Savic I, Strömberg J, Timby E, van Broekhoven F, van Wingen G (Feb 2014). "Allopregnanolone and mood disorders". Progress in Neurobiology 113: 88–94. doi:10.1016/j.pneurobio.2013.07.005. PMID 23978486.
- Rogawski MA, Reddy DS, 2004. Neurosteroids: endogenous modulators of seizure susceptibility. In: Rho, J.M., Sankar, R., Cavazos, J. (Eds.), Epilepsy: Scientific Foundations of Clinical Practice. Marcel Dekker, New York, 2004;319-355.
- Kokate TG, Yamaguchi S, Pannell LK, Rajamani U, Carroll DM, Grossman AB, Rogawski MA (Nov 1998). "Lack of anticonvulsant tolerance to the neuroactive steroid pregnanolone in mice". The Journal of Pharmacology and Experimental Therapeutics 287 (2): 553–8. PMID 9808680.
- Reddy DS, Rogawski MA (Dec 2000). "Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself". The Journal of Pharmacology and Experimental Therapeutics 295 (3): 1241–8. PMID 11082461.
- Reddy DS, Rogawski MA (Apr 2009). "Neurosteroid replacement therapy for catamenial epilepsy". Neurotherapeutics 6 (2): 392–401. doi:10.1016/j.nurt.2009.01.006. PMC 2682439. PMID 19332335.
- Orrin Devinsky, Steven Schachter, Steven Pacia (1 January 2005). Complementary and Alternative Therapies for Epilepsy. Demos Medical Publishing. pp. 378–. ISBN 978-1-934559-08-6.
- Griebel G, Holmes A (Sep 2013). "50 years of hurdles and hope in anxiolytic drug discovery" (PDF). Nature Reviews. Drug Discovery 12 (9): 667–87. doi:10.1038/nrd4075. PMID 23989795.
- Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, Guidotti A (Mar 1998). "Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine". Proceedings of the National Academy of Sciences of the United States of America 95 (6): 3239–44. doi:10.1073/pnas.95.6.3239. PMC 19726. PMID 9501247.
- Pinna G, Costa E, Guidotti A (Jun 2006). "Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake". Psychopharmacology 186 (3): 362–72. doi:10.1007/s00213-005-0213-2. PMID 16432684.
- Dhir A, Rogawski MA (Apr 2012). "Role of neurosteroids in the anticonvulsant activity of midazolam". British Journal of Pharmacology 165 (8): 2684–91. doi:10.1111/j.1476-5381.2011.01733.x. PMC 3423249. PMID 22014182.
- Usami N, Yamamoto T, Shintani S, Ishikura S, Higaki Y, Katagiri Y, Hara A (Apr 2002). "Substrate specificity of human 3(20)alpha-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines" (pdf). Biological & Pharmaceutical Bulletin 25 (4): 441–5. doi:10.1248/bpb.25.441. PMID 11995921.
- Akk G, Shu HJ, Wang C, Steinbach JH, Zorumski CF, Covey DF, Mennerick S (Dec 2005). "Neurosteroid access to the GABAA receptor". The Journal of Neuroscience 25 (50): 11605–13. doi:10.1523/JNEUROSCI.4173-05.2005. PMID 16354918.
- Wang JM, Johnston PB, Ball BG, Brinton RD (May 2005). "The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression". The Journal of Neuroscience 25 (19): 4706–18. doi:10.1523/JNEUROSCI.4520-04.2005. PMID 15888646.
- Dong E, Matsumoto K, Uzunova V, Sugaya I, Takahata H, Nomura H, Watanabe H, Costa E, Guidotti A (Feb 2001). "Brain 5alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation". Proceedings of the National Academy of Sciences of the United States of America 98 (5): 2849–54. doi:10.1073/pnas.051628598. PMC 30228. PMID 11226329.
- Melcangi RC, Celotti F, Martini L (Mar 1994). "Progesterone 5-alpha-reduction in neuronal and in different types of glial cell cultures: type 1 and 2 astrocytes and oligodendrocytes". Brain Research 639 (2): 202–6. doi:10.1016/0006-8993(94)91731-0. PMID 8205473.
- Corpéchot C, Robel P, Axelson M, Sjövall J, Baulieu EE (Aug 1981). "Characterization and measurement of dehydroepiandrosterone sulfate in rat brain". Proceedings of the National Academy of Sciences of the United States of America 78 (8): 4704–7. doi:10.1073/pnas.78.8.4704. PMC 320231. PMID 6458035.
- Reddy D, Rogawski MA (2012). "Neurosteroids — Endogenous regulators of seizure susceptibility and role in the treatment of epilepsy". In: Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012. Available from: http://www.ncbi.nlm.nih.gov/books/NBK98218/. PMID 22787590.