Neuroactive steroid
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/* Therapeutic application */
'''Neuroactive [[steroid]]s''' (or '''neurosteroids''') rapidly alter [[neuron]]al excitability through interaction with [[neurotransmitter]][[ligand-gated ion channel|-gated ion channel]]s.<ref name="pmid1347506">{{cite journal | author = Paul SM, Purdy RH | title = Neuroactive steroids | journal = FASEB J. | volume = 6 | issue = 6 | pages = 2311–22 | year = 1992 | pmid = 1347506 | doi = | issn = | url = http://www.fasebj.org/cgi/content/abstract/6/6/2311 | format = abstract }}</ref><ref name="pmid7729823">{{cite journal | author = Lan NC, Gee KW | title = Neuroactive steroid actions at the GABAA receptor | journal = Horm Behav | volume = 28 | issue = 4 | pages = 537–44 | year = 1994 | pmid = 7729823 | doi = 10.1006/hbeh.1994.1052 | issn = }}</ref> In addition, these steroids may also exert effects on [[gene expression]] via intracellular [[steroid hormone receptor]]s. Neurosteroids have a wide range of applications from [[sedation]] to treatment of [[epilepsy]] and [[traumatic brain injury]].<ref name="pmid17531324">{{cite journal | author = Morrow AL | title = Recent developments in the significance and therapeutic relevance of neuroactive steroids--Introduction to the special issue | journal = Pharmacol. Ther. | volume = 116 | issue = 1 | pages = 1–6 | year = 2007 | pmid = 17531324 | doi = 10.1016/j.pharmthera.2007.04.003 | issn = }}</ref><ref name="pmid15694225">{{cite journal | author = Dubrovsky BO | title = Steroids, neuroactive steroids and neurosteroids in psychopathology | journal = Prog. Neuropsychopharmacol. Biol. Psychiatry | volume = 29 | issue = 2 | pages = 169–92 | year = 2005 | pmid = 15694225 | doi = 10.1016/j.pnpbp.2004.11.001 | issn = }}</ref>
==Biosynthesis==
Several of these steroids accumulate in the brain after local synthesis or after metabolism of adrenal steroids. Neurosteroids are synthesized in the central and peripheral nervous system, especially in myelinating glial cells, from cholesterol or steroidal precursors imported from peripheral sources.<ref name="pmid16984997">{{cite journal | author = 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 = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 39 | pages = 14602–7 | year = 2006 | pmid = 16984997 | doi = 10.1073/pnas.0606544103 | issn = }}</ref><ref name="pmid11750861">{{cite journal | author = Mellon SH, Griffin LD | title = Neurosteroids: biochemistry and clinical significance | journal = Trends Endocrinol. Metab. | volume = 13 | issue = 1 | pages = 35–43 | year = 2002 | pmid = 11750861 | doi = 10.1016/S1043-2760(01)00503-3 | issn = }}</ref> They include 3β-hydroxy-Δ5 derivatives, such as [[pregnenolone]] (PREG) and [[dehydroepiandrosterone]] (DHEA), their sulfates, and reduced metabolites such as the tetrahydroderivative of progesterone 3α-hydroxy-5α-pregnane-20-one (3α,5α-THPROG).
==Mechanism==
These compounds can act as allosteric modulators of neurotransmitter receptors, such as [[GABAA receptor|GABA<sub>A</sub>]],<ref name="pmid2422758">{{cite journal | author = Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM | title = Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor | journal = Science | volume = 232 | issue = 4753 | pages = 1004–7 | year = 1986 | pmid = 2422758 | doi = 10.1126/science.2422758 | issn = }}</ref> <ref name="pmid17531325">{{cite journal | author = Herd MB, Belelli D, Lambert JJ | title = Neurosteroid modulation of synaptic and extrasynaptic GABA<sub>A</sub> receptors | journal = Pharmacology & Therapeutics| volume = 116| issue = | pages = 20| year = 2007 | pmid = 17531325 | doi = 10.1016/j.pharmthera.2007.03.007 | issn = }}</ref><ref name="pmid17108970">{{cite journal | author = Hosie AM, Wilkins ME, da Silva HM, Smart TG | title = Endogenous neurosteroids regulate GABA<sub>A</sub> receptors through two discrete transmembrane sites | journal = Nature | volume = 444 | issue = 7118 | pages = 486–9 | year = 2006 | pmid = 17108970 | doi = 10.1038/nature05324 | issn = }}</ref><ref name="pmid2160838">{{cite journal | author = Puia G, Santi MR, Vicini S, Pritchett DB, Purdy RH, Paul SM, Seeburg PH, Costa E | title = Neurosteroids act on recombinant human GABA<sub>A</sub> receptors | journal = Neuron | volume = 4 | issue = 5 | pages = 759–65 | year = 1990 | pmid = 2160838 | doi = | issn = }}</ref> [[NMDA receptor|NMDA]],<ref name="pmid1654510">{{cite journal | author = Wu FS, Gibbs TT, Farb DH | title = Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor | journal = Mol. Pharmacol. | volume = 40 | issue = 3 | pages = 333–6 | year = 1991 | pmid = 1654510 | doi = | issn = | url = http://molpharm.aspetjournals.org/cgi/content/abstract/40/3/333 | format = abstract }}</ref> and [[sigma receptor]]s.<ref name="pmid9062676">{{cite journal | author = Maurice T, Junien JL, Privat A | title = Dehydroepiandrosterone sulfate attenuates dizocilpine-induced learning impairment in mice via sigma 1-receptors | journal = Behav. Brain Res. | volume = 83 | issue = 1-2 | pages = 159–64 | year = 1997 | pmid = 9062676 | doi = | issn = }}</ref> [[Progesterone]] (PROG) is also a neurosteroid which activates [[progesterone receptor]]s expressed in peripheral and central glial cells.<ref name="pmid9238846">{{cite journal | author = Baulieu EE | title = Neurosteroids: of the nervous system, by the nervous system, for the nervous system | journal = Recent Prog. Horm. Res. | volume = 52 | issue = | pages = 1–32 | year = 1997 | pmid = 9238846 | doi = | issn = }}</ref><ref name="pmid8398145">{{cite journal | author = Rupprecht R, Reul JM, Trapp T, van Steensel B, Wetzel C, Damm K, Zieglgänsberger W, Holsboer F | title = Progesterone receptor-mediated effects of neuroactive steroids | journal = Neuron | volume = 11 | issue = 3 | pages = 523–30 | year = 1993 | pmid = 8398145 | doi = | issn = }}</ref><ref name="pmid10418983">{{cite journal | author = Jung-Testas I, Do Thi A, Koenig H, Désarnaud F, Shazand K, Schumacher M, Baulieu EE | title = Progesterone as a neurosteroid: synthesis and actions in rat glial cells | journal = J. Steroid Biochem. Mol. Biol. | volume = 69 | issue = 1-6 | pages = 97–107 | year = 1999 | pmid = 10418983 | doi = | issn = }}</ref><ref name="pmid15959466">{{cite journal | author = Belelli D, Lambert JJ | title = Neurosteroids: endogenous regulators of the GABA<sub>A</sub> receptor | journal = Nat. Rev. Neurosci. | volume = 6 | issue = 7 | pages = 565–75 | year = 2005 | pmid = 15959466 | doi = 10.1038/nrn1703 | issn = }}</ref> The 3α-hydroxy ring A-reduced pregnane steroids [[allopregnanolone]] and [[tetrahydrodeoxycorticosterone]] have been surmised to enhance [[GABA]]-mediated chloride currents, whereas [[pregnenolone]] sulfate and [[dehydroepiandrosterone]] (DHEA) sulfate display functional antagonistic properties at GABA<sub>A</sub> receptors.
==Therapeutic application==
Several synthetic neurosteroids have been used as [[sedative]]s for the purpose of [[general anaesthesia]] for carrying out surgical procedures. The best known of these are [[alphaxolone]], [[althesin|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 steriods. 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.
[[Image:neuroactive_steroids.png]]
==Role in antidepressant action==
Certain [[antidepressant]] drugs such as [[fluoxetine]] and [[fluvoxamine]] which were thought to act primarily as [[selective serotonin reuptake inhibitor]]s have also been found to increase the levels of certain neurosteroids.<ref name="pmid9501247">{{cite journal | author = Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, Guidotti A | title = Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 6 | pages = 3239–44 | year = 1998 | pmid = 9501247 | doi = 10.1073/pnas.95.6.3239 | issn = }}</ref><ref name="pmid16432684">{{cite journal | author = Pinna G, Costa E, Guidotti A | title = Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake | journal = Psychopharmacology (Berl.) | volume = 186 | issue = 3 | pages = 362–72 | year = 2006 | pmid = 16432684 | doi = 10.1007/s00213-005-0213-2 | issn = }}</ref> Based on these studies, it has been proposed that increased levels of neurosteroids induced by fluoxetine or fluvoxamine may significantly contribute to or even be the predominate mechanism of action of these antidepressant drugs.
===Benzodiazepines and effect on neurosteroids===
[[Benzodiazepines]] may influence neurosteroid metabolism and [[progesterone]] levels which in turn may influence the functions of the [[brain]]. The [[pharmacological]] actions of benzodiazepines at the GABAa receptor are similar to those of [[neurosteroids]]. [[Neuroactive]] steroids are positive [[allosteric]] modulators of the GABAa receptor, enhancing [[GABA]] function. Many benzodiazepines ([[diazepam]], [[medazepam]], [[estazolam]], [[nitrazepam]] [[flunitrazepam]] and [[temazepam]]) potently inhibit the [[enzymes]] involved in the [[metabolism]] of neurosteroids. Long-term administration of benzodiazepines may influence the concentrations of [[endogenous]] neurosteroids, and thereby would modulate the emotional state. Factors which effects the ability of individual benzodiazepines to alter neurosteroid levels depend on the molecular make up of the individual benzodiazepine drug. Presence of a substituent at N1 position of the [[diazepine]] ring and/or the chloro or nitro group at position 7 of the [[benzene]] ring contribute to potent inhibition of the isoenzymes, and in turn a [[bromo]] group at position 7 (for [[bromazepam]]) and additional substituents (3-hydroxy group for [[oxazepam]] and tetrahydroxazole ring for [[cloxazolam]] and [[oxazolam]]) decrease the [[inhibitory]] potency of benzodiazepines on neurosteroids.<ref>{{cite journal |author=Usami N |coauthors=Yamamoto T, Shintani S, Ishikura S, Higaki Y, Katagiri Y, Hara A |year=2002 |month=Apr |title=Substrate specificity of human 3(20)alpha-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines |journal=Biol Pharm Bull |volume=25 |issue=4 |pages=441-5 |pmid=11995921 |url=http://www.jstage.jst.go.jp/article/bpb/25/4/441/_pdf |format=pdf |doi=10.1248/bpb.25.441}}</ref>
==Further reading==
<ref name="pmid16354918">{{cite journal | author = Akk G, Shu HJ, Wang C, Steinbach JH, Zorumski CF, Covey DF, Mennerick S | title = Neurosteroid access to the GABA<sub>A</sub> receptor | journal = J. Neurosci. | volume = 25 | issue = 50 | pages = 11605–13 | year = 2005 | pmid = 16354918 | doi = 10.1523/JNEUROSCI.4173-05.2005 | issn = }}</ref> <ref name="pmid15888646">{{cite journal | author = Wang JM, Johnston PB, Ball BG, Brinton RD | title = The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression | journal = J. Neurosci. | volume = 25 | issue = 19 | pages = 4706–18 | year = 2005 | pmid = 15888646 | doi = 10.1523/JNEUROSCI.4520-04.2005 | issn = }}</ref> <ref name="pmid11226329">{{cite journal | author = Dong E, Matsumoto K, Uzunova V, Sugaya I, Takahata H, Nomura H, Watanabe H, Costa E, Guidotti A | title = Brain 5alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 98 | issue = 5 | pages = 2849–54 | year = 2001 | pmid = 11226329 | doi = 10.1073/pnas.051628598 | issn = }}</ref> <ref name="pmid8205473">{{cite journal | author = Melcangi RC, Celotti F, Martini L | title = Progesterone 5-alpha-reduction in neuronal and in different types of glial cell cultures: type 1 and 2 astrocytes and oligodendrocytes | journal = Brain Res. | volume = 639 | issue = 2 | pages = 202–6 | year = 1994 | pmid = 8205473 | doi = 10.1016/0006-8993(94)91731-0 | issn = }}</ref> <ref name="pmid6458035">{{cite journal | author = Corpéchot C, Robel P, Axelson M, Sjövall J, Baulieu EE | title = Characterization and measurement of dehydroepiandrosterone sulfate in rat brain | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 78 | issue = 8 | pages = 4704–7 | year = 1981 | pmid = 6458035 | doi = | issn = }}</ref>
==References==
{{Reflist|2}}
==See also==
*[[5-alpha reductase]]
*[[GABA A receptor]]
[[Category:Neurosteroids|*]]
[[Category:Steroids]]
[[Category:Neurophysiology]]
[[pl:Neurosteroidy]]