Neuroactive steroids, also known as neurosteroids, are endogenous 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. In contrast, neuroactive steroid refers to steroids that are synthesized by an endocrine gland that then reach the brain through the bloodstream and have effects on brain function. 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 References
- 8 Further reading
Classifications and mechanisms
These neurosteroids exert inhibitory actions on neurotransmission. They act as potent 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 (DHP)
- Allopregnanolone (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 agonists of the σ1 receptor, and have antidepressant, anxiogenic, cognitive and memory-enhancing, convulsant, neuroprotective, and neurogenic effects.
Certain other endogenous steroids, such as pregnenolone, progesterone, and estradiol, 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, 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 (1992). "Neuroactive steroids" (abstract). FASEB J. 6 (6): 2311–22. PMID 1347506.
- Lan NC, Gee KW (1994). "Neuroactive steroid actions at the GABA-A receptor". Horm Behav 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". Prog. Brain Res. 186: 113–37. doi:10.1016/B978-0-444-53630-3.00008-7. PMC 3139029. PMID 21094889.
- Srivastava DP, Waters EM, Mermelstein PG, Kramár EA, Shors TJ, Liu F (November 2011). "Rapid estrogen signaling in the brain: implications for the fine-tuning of neuronal circuitry". J. Neurosci. 31 (45): 16056–63. doi:10.1523/JNEUROSCI.4097-11.2011. PMC 3245715. PMID 22072656.
- Reddy DS, Rogawski MA (April 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 (2007). "Recent Developments in the Significance and Therapeutic Relevance of Neuroactive Steroids – Introduction to the Special Issue". Pharmacol. Ther. 116 (1): 1–6. doi:10.1016/j.pharmthera.2007.04.003. PMC 2047816. PMID 17531324.
- Dubrovsky BO (2005). "Steroids, neuroactive steroids and neurosteroids in psychopathology". Prog. Neuropsychopharmacol. Biol. 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 (2013). ""Ganaxolone" in Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS: Progress report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI)". Epilepsy Res. 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 (July 2002). "The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens". Eur. J. Neurosci. 16 (1): 169–73. doi:10.1046/j.1460-9568.2002.02084.x. PMID 12153544.
- Frye CA (December 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 (February 2005). "Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior". Proc. Natl. Acad. Sci. U.S.A. 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 (October 2012). "Steroid hormones and sleep regulation". Mini Rev Med Chem 12 (11): 1040–8. doi:10.2174/138955712802762167. PMID 23092405.
- Patte-Mensah C, Meyer L, Taleb O, Mensah-Nyagan AG (February 2014). "Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain". Prog. Neurobiol. 113: 70–8. doi:10.1016/j.pneurobio.2013.07.004. PMID 23948490.
- Marx CE, Bradford DW, Hamer RM, et al. (September 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 (2006). "Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis". Proc. Natl. Acad. Sci. U.S.A. 103 (39): 14602–7. doi:10.1073/pnas.0606544103. PMC 1600006. PMID 16984997.
- Mellon SH, Griffin LD (2002). "Neurosteroids: biochemistry and clinical significance". Trends Endocrinol. Metab. 13 (1): 35–43. doi:10.1016/S1043-2760(01)00503-3. PMID 11750861.
- Benarroch EE (March 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". Int. Rev. Neurobiol. 46: 273–320. doi:10.1016/s0074-7742(01)46066-1. PMID 11599303.
- Engel SR, Grant KA (2001). "Neurosteroids and behavior". Int. Rev. Neurobiol. 46: 321–48. PMID 11599304.
- King SR (2008). "Emerging roles for neurosteroids in sexual behavior and function". J. Androl. 29 (5): 524–33. doi:10.2164/jandrol.108.005660. PMID 18567641.
- Joshi S, Rajasekaran K, Kapur J (June 2013). "GABAergic transmission in temporal lobe epilepsy: the role of neurosteroids". Exp. Neurol. 244: 36–42. doi:10.1016/j.expneurol.2011.10.028. PMC 3319002. PMID 22101060.
- Girdler SS, Klatzkin R (October 2007). "Neurosteroids in the context of stress: implications for depressive disorders". Pharmacol. Ther. 116 (1): 125–39. doi:10.1016/j.pharmthera.2007.05.006. PMC 2650267. PMID 17597217.
- Bali A, Jaggi AS (January 2014). "Multifunctional aspects of allopregnanolone in stress and related disorders". Prog. Neuropsychopharmacol. Biol. Psychiatry 48: 64–78. doi:10.1016/j.pnpbp.2013.09.005. PMID 24044974.
- Gunn BG, Cunningham L, Mitchell S, Swinny JD, Lambert JJ, Belelli D (June 2014). "GABAA receptor-acting neurosteroids: A role in the development and regulation of the stress response". Front Neuroendocrinol. doi:10.1016/j.yfrne.2014.06.001. PMID 24929099.
- Bäckström T, Andersson A, Andreé L, et al. (December 2003). "Pathogenesis in menstrual cycle-linked CNS disorders". Ann. N. Y. Acad. Sci. 1007: 42–53. PMID 14993039.
- Guille C, Spencer S, Cavus I, Epperson CN (July 2008). "The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: implications for diagnosis and treatment". Epilepsy Behav 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". Neurol. Sci. 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". Ann. N. Y. Acad. Sci. 900: 1–9. PMID 10818386.
- Melcangi RC, Panzica G, Garcia-Segura LM (September 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 (August 2006). "Allopregnanolone concentration and mood--a bimodal association in postmenopausal women treated with oral progesterone". Psychopharmacology (Berl.) 187 (2): 209–21. doi:10.1007/s00213-006-0417-0. PMID 16724185.
- Bäckström T, Haage D, Löfgren M, et al. (September 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 (September 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, et al. (February 2014). "Allopregnanolone and mood disorders". Prog. Neurobiol. 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 (November 1998). "Lack of anticonvulsant tolerance to the neuroactive steroid pregnanolone in mice". J. Pharmacol. Exp. Ther. 287 (2): 553–8. PMID 9808680.
- Reddy DS, Rogawski MA (December 2000). "Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself". J. Pharmacol. Exp. Ther. 295 (3): 1241–8. PMID 11082461.
- Reddy DS, Rogawski MA (April 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.
- Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, Guidotti A (1998). "Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine". Proc. Natl. Acad. Sci. U.S.A. 95 (6): 3239–44. doi:10.1073/pnas.95.6.3239. PMC 19726. PMID 9501247.
- Pinna G, Costa E, Guidotti A (2006). "Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake". Psychopharmacology (Berl.) 186 (3): 362–72. doi:10.1007/s00213-005-0213-2. PMID 16432684.
- Dhir A, Rogawski MA (October 2011). "Role of neurosteroids in the anticonvulsant activity of midazolam". Br J Pharmacol 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 (April 2002). "Substrate specificity of human 3(20)alpha-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines" (pdf). Biol Pharm Bull 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 (2005). "Neurosteroid access to the GABAA receptor". J. Neurosci. 25 (50): 11605–13. doi:10.1523/JNEUROSCI.4173-05.2005. PMID 16354918.
- Wang JM, Johnston PB, Ball BG, Brinton RD (2005). "The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression". J. Neurosci. 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 (2001). "Brain 5α-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation". Proc. Natl. Acad. Sci. U.S.A. 98 (5): 2849–54. doi:10.1073/pnas.051628598. PMC 30228. PMID 11226329.
- Melcangi RC, Celotti F, Martini L (1994). "Progesterone 5-alpha-reduction in neuronal and in different types of glial cell cultures: type 1 and 2 astrocytes and oligodendrocytes". Brain Res. 639 (2): 202–6. doi:10.1016/0006-8993(94)91731-0. PMID 8205473.
- Corpéchot C, Robel P, Axelson M, Sjövall J, Baulieu EE (1981). "Characterization and measurement of dehydroepiandrosterone sulfate in rat brain". Proc. Natl. Acad. Sci. U.S.A. 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.