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{{BioPsy}} |
{{BioPsy}} |
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| − | '''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 |
+ | '''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 = | 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 GABA-A receptor | journal = Horm Behav | volume = 28 | issue = 4 | pages = 537–44 | year = 1994 | pmid = 7729823 | doi = 10.1006/hbeh.1994.1052 }}</ref> In addition, these steroids may also exert effects on [[gene expression]] via intracellular [[steroid hormone receptor]]s. Neurosteroids have a wide range of potential clinical applications from [[sedation]] to treatment of [[epilepsy]]<ref>{{cite journal |PMID= 19332335 | doi=10.1016/j.nurt.2009.01.006 | pmc=2682439 | pmid=19332335 | volume=6 | issue=2 | title=Neurosteroid replacement therapy for catamenial epilepsy | year=2009 | month=April | journal=Neurotherapeutics | pages=392–401 | author=Reddy DS, Rogawski MA}}</ref> 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| pmc = 2047816 }}</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 }}</ref> [[Ganaxolone]], an analog of the endogenous neurosteroid [[allopregnanolone]], is under investigation for the treatment of epilepsy.<ref name="pmid23219031">{{cite journal | author = Farfel G, Tsai J, Shaw K, Nohria V, Rogawski MA | title = "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) | journal = Epilepsy Res. | volume = 103 | pages = 2–30 | year = 2013 | pmid = 23219031 | doi=10.1016/j.eplepsyres.2012.10.001}}</ref> |
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| − | Apart from exerting effects on the [[genome]] via intracellular steroid [[Receptor (biochemistry)|receptors]], '''neuroactive [[steroid]]s''' rapidly alter [[neuron]]al excitability through interaction with [[neurotransmitter]]-gated [[ion channels]]. Several of these steroids accumulate in the brain after local synthesis or after metabolism of adrenal steroids. The 3alpha-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 A receptor]]s. |
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==Biosynthesis== |
==Biosynthesis== |
||
| − | Several of these steroids accumulate in the brain after local synthesis or after metabolism of adrenal steroids or gonadal steroids, especially testosterone. 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 |
+ | Several of these steroids accumulate in the brain after local synthesis or after metabolism of adrenal steroids or gonadal steroids, especially testosterone. 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| pmc = 1600006 }}</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 }}</ref> They include 3β-hydroxy-Δ5 derivatives, such as [[pregnenolone]] (PREG) and [[dehydroepiandrosterone]] (DHEA), their sulfates, and reduced metabolites such as the tetrahydro derivative of progesterone 3α-hydroxy-5α-pregnane-20-one (3α,5α-THPROG). |
==Mechanism== |
==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 |
+ | 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 }}</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 = 1| pages = 20–34| year = 2007 | pmid = 17531325 | doi = 10.1016/j.pharmthera.2007.03.007 }}</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 }}</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 = 10.1016/0896-6273(90)90202-Q }}</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 = | 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 = 10.1016/S0166-4328(97)86061-5 }}</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 = [[Étienne-Émile Baulieu|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 = }}</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 = 10.1016/0896-6273(93)90156-L }}</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 = 10.1016/S0960-0760(98)00149-6 }}</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 }}</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== |
==Therapeutic application== |
||
| + | [[Image:neuroactive steroids.png|thumb|frame|Older clinically used synthetic neuroactive steroids.]] |
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| + | |||
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 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. |
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 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. |
||
| + | [[File:Ganaxolone-200px.png|thumb|left|Ganaxolone, a neuroactive steroid currently in clinical development]] |
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| − | [[Image:neuroactive steroids.png]] |
||
| + | 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.<ref>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.</ref> They may have advantages over other GABA<sub>A</sub> receptor modulators, notably benzodiazepines, in that tolerance does not appear to occur with extended use.<ref>{{cite journal | pmid = 9808680 | volume=287 | issue=2 | title=Lack of anticonvulsant tolerance to the neuroactive steroid pregnanolone in mice | year=1998 | month=November | journal=J. Pharmacol. Exp. Ther. | pages=553–8 | author=Kokate TG, Yamaguchi S, Pannell LK, ''et al.''}}</ref><ref>{{cite journal | pmid = 11082461 | volume=295 | issue=3 | title=Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself | year=2000 | month=December | journal=J. Pharmacol. Exp. Ther. | pages=1241–8 | author=Reddy DS, Rogawski MA}}</ref> |
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| − | More recently, another neurosteroid [[ganaxolone]] has been developed and is currently in clinical trials for the treatment of [[epilepsy]]. This drug has less [[sedative]] effects than the anaesthetic neurosteroids listed above, but is a potent [[anticonvulsant]] which may have some advantages over older anticonvulsant drugs, mainly less development of tolerance with extended use. |
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| + | 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.<ref name="pmid23219031" /> 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. |
||
==Role in antidepressant action== |
==Role in antidepressant action== |
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| − | Certain [[antidepressant]] drugs such as [[fluoxetine]] and [[fluvoxamine]] which |
+ | Certain [[antidepressant]] drugs such as [[fluoxetine]] and [[fluvoxamine]] which are generally 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| pmc = 19726 }}</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 }}</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 predominant mechanism of action of these antidepressant drugs. |
| − | == |
+ | ==Benzodiazepine effects on neurosteroids== |
| − | [[Benzodiazepines]] may influence neurosteroid metabolism |
+ | [[Benzodiazepines]] may influence neurosteroid metabolism by virtue of their actions on [[translocator protein]] (TSPO; "peripheral benzodiazepine receptor").<ref name:"pmid22014182">{{cite journal | author = Dhir A, Rogawski MA | title = Role of neurosteroids in the anticonvulsant activity of midazolam | journal = Br J Pharmacol | year = 2011 | month = October | doi = 10.1111/j.1476-5381.2011.01733.x | pmid = 22014182}}</ref> The [[pharmacological]] actions of benzodiazepines at the GABA<sub>A</sub> 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.<ref>{{cite journal |author=Usami N |coauthors=Yamamoto T, Shintani S, Ishikura S, Higaki Y, Katagiri Y, Hara A |year=2002 |month=April |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> |
| + | |||
| + | ==Examples== |
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| + | * [[Allopregnanolone]] |
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| + | * [[Dehydroepiandrosterone]] |
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| + | * [[Dehydroepiandrosterone sulfate]] |
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| + | * [[5α-Dihydroprogesterone]] |
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| + | * [[Pregnenolone]] |
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| + | * [[Progesterone]] |
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| + | * [[Tetrahydrodeoxycorticosterone]] |
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==Antagonists== |
==Antagonists== |
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{{Hypnotics and sedatives}} |
{{Hypnotics and sedatives}} |
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{{GABAergics}} |
{{GABAergics}} |
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| ⚫ | |||
| − | [[Category:Steroids]] |
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| − | [[Category:Neurophysiology]] |
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| − | [[pl:Neurosteroidy]] |
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| − | [[ru:Нейростероид]] |
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==External links== |
==External links== |
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| ⚫ | |||
[[Category:Steroids]] |
[[Category:Steroids]] |
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[[Category:Neurophysiology]] |
[[Category:Neurophysiology]] |
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Latest revision as of 23:16, 24 July 2013
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Biological: Behavioural genetics · Evolutionary psychology · Neuroanatomy · Neurochemistry · Neuroendocrinology · Neuroscience · Psychoneuroimmunology · Physiological Psychology · Psychopharmacology (Index, Outline)
Neuroactive steroids (or neurosteroids) rapidly alter neuronal excitability through interaction with neurotransmitter-gated ion channels.[1][2] In addition, these steroids may also exert effects on gene expression via intracellular steroid hormone receptors. Neurosteroids have a wide range of potential clinical applications from sedation to treatment of epilepsy[3] and traumatic brain injury.[4][5] Ganaxolone, an analog of the endogenous neurosteroid allopregnanolone, is under investigation for the treatment of epilepsy.[6]
Biosynthesis
Several of these steroids accumulate in the brain after local synthesis or after metabolism of adrenal steroids or gonadal steroids, especially testosterone. Neurosteroids are synthesized in the central and peripheral nervous system, especially in myelinating glial cells, from cholesterol or steroidal precursors imported from peripheral sources.[7][8] They include 3β-hydroxy-Δ5 derivatives, such as pregnenolone (PREG) and dehydroepiandrosterone (DHEA), their sulfates, and reduced metabolites such as the tetrahydro derivative 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,[9][10][11][12] NMDA,[13] and sigma receptors.[14] Progesterone (PROG) is also a neurosteroid which activates progesterone receptors expressed in peripheral and central glial cells.[15][16][17][18] 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 GABAA receptors.
Therapeutic application
Older clinically used synthetic neuroactive steroids.
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.
Ganaxolone, a neuroactive steroid currently in clinical development
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.[19] They may have advantages over other GABAA receptor modulators, notably benzodiazepines, in that tolerance does not appear to occur with extended use.[20][21] 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.[6] 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.
Role in antidepressant action
Certain antidepressant drugs such as fluoxetine and fluvoxamine which are generally thought to act primarily as selective serotonin reuptake inhibitors have also been found to increase the levels of certain neurosteroids.[22][23] 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 predominant mechanism of action of these antidepressant drugs.
Benzodiazepine effects on neurosteroids
Benzodiazepines may influence neurosteroid metabolism by virtue of their actions on translocator protein (TSPO; "peripheral benzodiazepine receptor").[24] 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.[25]
Examples
- Allopregnanolone
- Dehydroepiandrosterone
- Dehydroepiandrosterone sulfate
- 5α-Dihydroprogesterone
- Pregnenolone
- Progesterone
- Tetrahydrodeoxycorticosterone
Antagonists
- 17-Phenylandrostenol - blocks the effects of neuroactive steroids without affecting responses produced by benzodiazepines or barbiturates
See also
References
- ↑ Paul SM, Purdy RH (1992). Neuroactive steroids. FASEB J. 6 (6): 2311–22.
- ↑ Lan NC, Gee KW (1994). Neuroactive steroid actions at the GABA-A receptor. Horm Behav 28 (4): 537–44.
- ↑ Reddy DS, Rogawski MA (April 2009). Neurosteroid replacement therapy for catamenial epilepsy. Neurotherapeutics 6 (2): 392–401.
- ↑ 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.
- ↑ Dubrovsky BO (2005). Steroids, neuroactive steroids and neurosteroids in psychopathology. Prog. Neuropsychopharmacol. Biol. Psychiatry 29 (2): 169–92.
- ↑ 6.0 6.1 Farfel G, Tsai J, Shaw K, Nohria V, Rogawski MA (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: 2–30.
- ↑ 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.
- ↑ Mellon SH, Griffin LD (2002). Neurosteroids: biochemistry and clinical significance. Trends Endocrinol. Metab. 13 (1): 35–43.
- ↑ Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM (1986). Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 232 (4753): 1004–7.
- ↑ Herd MB, Belelli D, Lambert JJ (2007). Neurosteroid modulation of synaptic and extrasynaptic GABAA receptors. Pharmacology & Therapeutics 116 (1): 20–34.
- ↑ Hosie AM, Wilkins ME, da Silva HM, Smart TG (2006). Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature 444 (7118): 486–9.
- ↑ Puia G, Santi MR, Vicini S, Pritchett DB, Purdy RH, Paul SM, Seeburg PH, Costa E (1990). Neurosteroids act on recombinant human GABAA receptors. Neuron 4 (5): 759–65.
- ↑ Wu FS, Gibbs TT, Farb DH (1991). Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor. Mol. Pharmacol. 40 (3): 333–6.
- ↑ Maurice T, Junien JL, Privat A (1997). Dehydroepiandrosterone sulfate attenuates dizocilpine-induced learning impairment in mice via sigma 1-receptors. Behav. Brain Res. 83 (1–2): 159–64.
- ↑ Baulieu EE (1997). Neurosteroids: of the nervous system, by the nervous system, for the nervous system. Recent Prog. Horm. Res. 52: 1–32.
- ↑ Rupprecht R, Reul JM, Trapp T, van Steensel B, Wetzel C, Damm K, Zieglgänsberger W, Holsboer F (1993). Progesterone receptor-mediated effects of neuroactive steroids. Neuron 11 (3): 523–30.
- ↑ Jung-Testas I, Do Thi A, Koenig H, Désarnaud F, Shazand K, Schumacher M, Baulieu EE (1999). Progesterone as a neurosteroid: synthesis and actions in rat glial cells. J. Steroid Biochem. Mol. Biol. 69 (1–6): 97–107.
- ↑ Belelli D, Lambert JJ (2005). Neurosteroids: endogenous regulators of the GABAA receptor. Nat. Rev. Neurosci. 6 (7): 565–75.
- ↑ 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, et al. (November 1998). Lack of anticonvulsant tolerance to the neuroactive steroid pregnanolone in mice. J. Pharmacol. Exp. Ther. 287 (2): 553–8.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Dhir A, Rogawski MA (October 2011). Role of neurosteroids in the anticonvulsant activity of midazolam. Br J Pharmacol.
- ↑ 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. Biol Pharm Bull 25 (4): 441–5.
Further reading
- 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.
- 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.
- Dong E, Matsumoto K, Uzunova V, Sugaya I, Takahata H, Nomura H, Watanabe H, Costa E, Guidotti A (2001). Brain 5alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation. Proc. Natl. Acad. Sci. U.S.A. 98 (5): 2849–54.
- 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.
- 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.</ref>
Psycholeptics: hypnotics and sedatives (N05C)
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| Barbiturates | Pentobarbital - Amobarbital - Butobarbital - Barbital - Aprobarbital - Secobarbital - Talbutal - Vinylbital - Vinbarbital - Cyclobarbital - Heptabarbital - Reposal - Methohexital - Hexobarbital - Thiopental Ethallobarbital - Allobarbital - Proxibarbal - Phenobarbital |
| Aldehydes | Chloral hydrate - Chloralodol - Acetylglycinamide chloral hydrate - Dichloralphenazone - Paraldehyde |
| Benzodiazepine | Flurazepam - Nitrazepam - Temazepam - Flunitrazepam - Nimetazepam - Estazolam - Triazolam - Lormetazepam - Midazolam - Brotizolam - Quazepam - Loprazolam - Doxefazepam - Cinolazepam |
| Piperidinedione | Glutethimide - Methyprylon - Pyrithyldione |
| Nonbenzodiazepine | Zopiclone/Eszopiclone - Zolpidem - Zaleplon |
| Melatonin receptor | Melatonin - Ramelteon |
| Other | Methaqualone - Clomethiazole - Bromisoval - Carbromal - Scopolamine - Propiomazine - Triclofos - Ethchlorvynol - Valerian - Hexapropymate - Bromides - Apronal - Valnoctamide - Methylpentynol - Niaprazine - Dexmedetomidine |
GABAergics | |||||||||||||||
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| Receptor ligands |
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| Reuptake inhibitors |
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| Enzyme inhibitors |
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| Others |
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External links
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