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Neurosteroidogenesis inhibitor

January 29, 2023

A neurosteroidogenesis inhibitor is a drug that inhibits the production of endogenous neurosteroids. Neurosteroids include the excitatory neurosteroids pregnenolone sulfate, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S), and the inhibitory neurosteroids allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), and 3α-androstanediol, among others.[1] By inhibiting the synthesis of endogenous neurosteroids, neurosteroidogenesis inhibitors have effects in the central nervous system.

Inhibitory neurosteroids are biosynthesized from steroid hormones by the action of two enzymes, 5α-reductase and 3α-hydroxysteroid dehydrogenase (3α-HSD).[1] These enzymes can be inhibited by 5α-reductase inhibitors such as finasteride and dutasteride and by inhibitors of 3α-HSD such as medroxyprogesterone acetate.[2][3][4] Contrarily, 3α-HSD is induced to varying extents by certain selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, fluvoxamine, sertraline, and paroxetine, as well as by certain other antidepressants like venlafaxine and mirtazapine, and these antidepressants have been found to increase inhibitory neurosteroid levels.[1][5][6][7] Inhibition of inhibitory neurosteroid biosynthesis by 5α-reductase inhibitors and 3α-HSD inhibitors has been associated with depression, anxiety, irritability, and sexual dysfunction,[2][4][8] whereas enhancement of their biosynthesis has been implicated in the antidepressant and anxiolytic effects of some of the SSRIs.[1]

Inhibitors of cholesterol side-chain cleavage enzyme (P450scc), such as aminoglutethimide and ketoconazole, may block production of both excitatory and inhibitory neurosteroids, while CYP17A1 (17α-hydroxylase/17,20 lyase) inhibitors, such as abiraterone acetate, may mainly block production of excitatory neurosteroids.[9] Antigonadotropins may also have the effect of lowering circulating neurosteroid levels.

The translocator protein (TSPO), also initially described as the peripheral benzodiazepine receptor (PBR), is a mitochondrial protein that is involved in neurosteroid biosynthesis.[10][11] It is activated by certain benzodiazepines such as diazepam and midazolam, and via this action, inhibitory neurosteroid levels are increased.[1][10][11] Selective TSPO activators, such as emapunil, are under investigation for clinical use as possible anxiolytics.[1]

Progesterone, which is the endogenous precursor to the inhibitory neurosteroids 5α-dihydroprogesterone and allopregnanolone, as well as, more distantly, THDOC,[1][12] when administered exogenously, has been found to behave as a prodrug to these neurosteroids,[13][14] with clinical signs of their action, such as sedation, readily evident in humans.[15][16][17] Exogenous pregnenolone has similarly been found to act as a prodrug of allopregnanolone.[18]

Metyrapone, a reversible inhibitor of the enzyme steroid 11β-hydroxylase, may increase inhibitory neurosteroid levels.[19] Conversely, it may inhibit the production of cortisol-derived excitatory neurosteroids.[9]

Paracetamol (acetaminophen; Tylenol) has been shown to act at SULT2A1 (and potentially at SULT2B1) as an inhibitor of neurosteroidogenesis.[20] Specifically, the production of sulfate-containing neurosteroids, such as DHEA-S and pregnenolone sulfate, were decreased in patients taking paracetamol.[20]

See also

References

  1. ^ a b c d e f g Reddy, Doodipala Samba (2010). "Neurosteroids". Sex Differences in the Human Brain, their Underpinnings and Implications. Progress in Brain Research. Vol. 186. pp. 113–137. doi:10.1016/B978-0-444-53630-3.00008-7. ISBN 9780444536303. ISSN 0079-6123. PMC 3139029. PMID 21094889.
  2. ^ a b Traish AM, Mulgaonkar A, Giordano N (June 2014). "The dark side of 5α-reductase inhibitors' therapy: sexual dysfunction, high Gleason grade prostate cancer and depression". Korean J Urol. 55 (6): 367–79. doi:10.4111/kju.2014.55.6.367. PMC 4064044. PMID 24955220.
  3. ^ Meyer L, Venard C, Schaeffer V, Patte-Mensah C, Mensah-Nyagan AG (April 2008). "The biological activity of 3alpha-hydroxysteroid oxido-reductase in the spinal cord regulates thermal and mechanical pain thresholds after sciatic nerve injury". Neurobiol. Dis. 30 (1): 30–41. doi:10.1016/j.nbd.2007.12.001. PMID 18291663. S2CID 5830825.
  4. ^ a b Pazol K, Wilson ME, Wallen K (June 2004). "Medroxyprogesterone acetate antagonizes the effects of estrogen treatment on social and sexual behavior in female macaques". J. Clin. Endocrinol. Metab. 89 (6): 2998–3006. doi:10.1210/jc.2003-032086. PMC 1440328. PMID 15181090.
  5. ^ Griffin LD, Mellon SH (November 1999). "Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes". Proc. Natl. Acad. Sci. U.S.A. 96 (23): 13512–7. doi:10.1073/pnas.96.23.13512. PMC 23979. PMID 10557352.
  6. ^ Pinna G (September 2010). "In a mouse model relevant for post-traumatic stress disorder, selective brain steroidogenic stimulants (SBSS) improve behavioral deficits by normalizing allopregnanolone biosynthesis". Behav Pharmacol. 21 (5–6): 438–50. doi:10.1097/FBP.0b013e32833d8ba0. PMC 2942072. PMID 20716970.
  7. ^ Schüle C, Romeo E, Uzunov DP, Eser D, di Michele F, Baghai TC, Pasini A, Schwarz M, Kempter H, Rupprecht R (March 2006). "Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha-hydroxysteroid dehydrogenase activity". Mol. Psychiatry. 11 (3): 261–72. doi:10.1038/sj.mp.4001782. PMID 16344854.
  8. ^ Civic D, Scholes D, Ichikawa L, et al. (June 2000). "Depressive symptoms in users and non-users of depot medroxyprogesterone acetate". Contraception. 61 (6): 385–90. doi:10.1016/s0010-7824(00)00122-0. PMID 10958882.
  9. ^ a b Tvrdeić, Ante; Poljak, Ljiljana (2016). "Neurosteroids, GABAA receptors and neurosteroid based drugs: are we witnessing the dawn of the new psychiatric drugs?". Endocrine Oncology and Metabolism. 2 (1): 60–71. doi:10.21040/eom/2016.2.7. ISSN 1849-8922.
  10. ^ a b Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapère JJ, Lindemann P, Norenberg MD, Nutt D, Weizman A, Zhang MR, Gavish M (August 2006). "Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function". Trends Pharmacol. Sci. 27 (8): 402–9. doi:10.1016/j.tips.2006.06.005. PMID 16822554.
  11. ^ a b 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.
  12. ^ Paul SM, Purdy RH (1992). "Neuroactive steroids". FASEB J. 6 (6): 2311–22. doi:10.1096/fasebj.6.6.1347506. PMID 1347506. S2CID 221753076.
  13. ^ Rebekah Wang-Cheng; Joan M. Neuner; Vanessa M. Barnabei (2007). Menopause. ACP Press. pp. 97–. ISBN 978-1-930513-83-9.
  14. ^ Niels Bergemann; Anita Riecher-Rössler (27 December 2005). Estrogen Effects in Psychiatric Disorders. Springer Science & Business Media. pp. 179–. ISBN 978-3-211-27063-9.
  15. ^ Söderpalm AH, Lindsey S, Purdy RH, Hauger R, Wit de H (2004). "Administration of progesterone produces mild sedative-like effects in men and women". Psychoneuroendocrinology. 29 (3): 339–54. doi:10.1016/s0306-4530(03)00033-7. PMID 14644065. S2CID 21796848.
  16. ^ de Wit H, Schmitt L, Purdy R, Hauger R (2001). "Effects of acute progesterone administration in healthy postmenopausal women and normally-cycling women". Psychoneuroendocrinology. 26 (7): 697–710. doi:10.1016/s0306-4530(01)00024-5. PMID 11500251. S2CID 20611661.
  17. ^ van Broekhoven F, Bäckström T, Verkes RJ (2006). "Oral progesterone decreases saccadic eye velocity and increases sedation in women". Psychoneuroendocrinology. 31 (10): 1190–9. doi:10.1016/j.psyneuen.2006.08.007. PMID 17034954. S2CID 40466952.
  18. ^ Sripada RK, Marx CE, King AP, Rampton JC, Ho SS, Liberzon I (2013). "Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits". Biol. Psychiatry. 73 (11): 1045–53. doi:10.1016/j.biopsych.2012.12.008. PMC 3648625. PMID 23348009.
  19. ^ Schmoutz CD, Guerin GF, Goeders NE (2014). "Role of GABA-active neurosteroids in the efficacy of metyrapone against cocaine addiction". Behav. Brain Res. 271: 269–76. doi:10.1016/j.bbr.2014.06.032. PMID 24959859. S2CID 37159095.
  20. ^ a b Cohen IV, Cirulli ET, Mitchell MW, Jonsson TJ, Yu J, Shah N, Spector TD, Guo L, Venter JC, Telenti A (2018). "Acetaminophen (Paracetamol) Use Modifies the Sulfation of Sex Hormones". EBioMedicine. 28: 316–323. doi:10.1016/j.ebiom.2018.01.033. PMC 5835573. PMID 29398597.

January 29, 2023
neurosteroidogenesis, inhibitor, neurosteroidogenesis, inhibitor, drug, that, inhibits, production, endogenous, neurosteroids, neurosteroids, include, excitatory, neurosteroids, pregnenolone, sulfate, dehydroepiandrosterone, dhea, dehydroepiandrosterone, sulfa. A neurosteroidogenesis inhibitor is a drug that inhibits the production of endogenous neurosteroids Neurosteroids include the excitatory neurosteroids pregnenolone sulfate dehydroepiandrosterone DHEA and dehydroepiandrosterone sulfate DHEA S and the inhibitory neurosteroids allopregnanolone tetrahydrodeoxycorticosterone THDOC and 3a androstanediol among others 1 By inhibiting the synthesis of endogenous neurosteroids neurosteroidogenesis inhibitors have effects in the central nervous system Inhibitory neurosteroids are biosynthesized from steroid hormones by the action of two enzymes 5a reductase and 3a hydroxysteroid dehydrogenase 3a HSD 1 These enzymes can be inhibited by 5a reductase inhibitors such as finasteride and dutasteride and by inhibitors of 3a HSD such as medroxyprogesterone acetate 2 3 4 Contrarily 3a HSD is induced to varying extents by certain selective serotonin reuptake inhibitors SSRIs including fluoxetine fluvoxamine sertraline and paroxetine as well as by certain other antidepressants like venlafaxine and mirtazapine and these antidepressants have been found to increase inhibitory neurosteroid levels 1 5 6 7 Inhibition of inhibitory neurosteroid biosynthesis by 5a reductase inhibitors and 3a HSD inhibitors has been associated with depression anxiety irritability and sexual dysfunction 2 4 8 whereas enhancement of their biosynthesis has been implicated in the antidepressant and anxiolytic effects of some of the SSRIs 1 Inhibitors of cholesterol side chain cleavage enzyme P450scc such as aminoglutethimide and ketoconazole may block production of both excitatory and inhibitory neurosteroids while CYP17A1 17a hydroxylase 17 20 lyase inhibitors such as abiraterone acetate may mainly block production of excitatory neurosteroids 9 Antigonadotropins may also have the effect of lowering circulating neurosteroid levels The translocator protein TSPO also initially described as the peripheral benzodiazepine receptor PBR is a mitochondrial protein that is involved in neurosteroid biosynthesis 10 11 It is activated by certain benzodiazepines such as diazepam and midazolam and via this action inhibitory neurosteroid levels are increased 1 10 11 Selective TSPO activators such as emapunil are under investigation for clinical use as possible anxiolytics 1 Progesterone which is the endogenous precursor to the inhibitory neurosteroids 5a dihydroprogesterone and allopregnanolone as well as more distantly THDOC 1 12 when administered exogenously has been found to behave as a prodrug to these neurosteroids 13 14 with clinical signs of their action such as sedation readily evident in humans 15 16 17 Exogenous pregnenolone has similarly been found to act as a prodrug of allopregnanolone 18 Metyrapone a reversible inhibitor of the enzyme steroid 11b hydroxylase may increase inhibitory neurosteroid levels 19 Conversely it may inhibit the production of cortisol derived excitatory neurosteroids 9 Paracetamol acetaminophen Tylenol has been shown to act at SULT2A1 and potentially at SULT2B1 as an inhibitor of neurosteroidogenesis 20 Specifically the production of sulfate containing neurosteroids such as DHEA S and pregnenolone sulfate were decreased in patients taking paracetamol 20 See also EditSteroidogenic enzyme Steroidogenesis inhibitor List of steroid metabolism modulatorsReferences Edit a b c d e f g Reddy Doodipala Samba 2010 Neurosteroids Sex Differences in the Human Brain their Underpinnings and Implications Progress in Brain Research Vol 186 pp 113 137 doi 10 1016 B978 0 444 53630 3 00008 7 ISBN 9780444536303 ISSN 0079 6123 PMC 3139029 PMID 21094889 a b Traish AM Mulgaonkar A Giordano N June 2014 The dark side of 5a reductase inhibitors therapy sexual dysfunction high Gleason grade prostate cancer and depression Korean J Urol 55 6 367 79 doi 10 4111 kju 2014 55 6 367 PMC 4064044 PMID 24955220 Meyer L Venard C Schaeffer V Patte Mensah C Mensah Nyagan AG April 2008 The biological activity of 3alpha hydroxysteroid oxido reductase in the spinal cord regulates thermal and mechanical pain thresholds after sciatic nerve injury Neurobiol Dis 30 1 30 41 doi 10 1016 j nbd 2007 12 001 PMID 18291663 S2CID 5830825 a b Pazol K Wilson ME Wallen K June 2004 Medroxyprogesterone acetate antagonizes the effects of estrogen treatment on social and sexual behavior in female macaques J Clin Endocrinol Metab 89 6 2998 3006 doi 10 1210 jc 2003 032086 PMC 1440328 PMID 15181090 Griffin LD Mellon SH November 1999 Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes Proc Natl Acad Sci U S A 96 23 13512 7 doi 10 1073 pnas 96 23 13512 PMC 23979 PMID 10557352 Pinna G September 2010 In a mouse model relevant for post traumatic stress disorder selective brain steroidogenic stimulants SBSS improve behavioral deficits by normalizing allopregnanolone biosynthesis Behav Pharmacol 21 5 6 438 50 doi 10 1097 FBP 0b013e32833d8ba0 PMC 2942072 PMID 20716970 Schule C Romeo E Uzunov DP Eser D di Michele F Baghai TC Pasini A Schwarz M Kempter H Rupprecht R March 2006 Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha hydroxysteroid dehydrogenase activity Mol Psychiatry 11 3 261 72 doi 10 1038 sj mp 4001782 PMID 16344854 Civic D Scholes D Ichikawa L et al June 2000 Depressive symptoms in users and non users of depot medroxyprogesterone acetate Contraception 61 6 385 90 doi 10 1016 s0010 7824 00 00122 0 PMID 10958882 a b Tvrdeic Ante Poljak Ljiljana 2016 Neurosteroids GABAA receptors and neurosteroid based drugs are we witnessing the dawn of the new psychiatric drugs Endocrine Oncology and Metabolism 2 1 60 71 doi 10 21040 eom 2016 2 7 ISSN 1849 8922 a b Papadopoulos V Baraldi M Guilarte TR Knudsen TB Lacapere JJ Lindemann P Norenberg MD Nutt D Weizman A Zhang MR Gavish M August 2006 Translocator protein 18kDa new nomenclature for the peripheral type benzodiazepine receptor based on its structure and molecular function Trends Pharmacol Sci 27 8 402 9 doi 10 1016 j tips 2006 06 005 PMID 16822554 a b 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 Paul SM Purdy RH 1992 Neuroactive steroids FASEB J 6 6 2311 22 doi 10 1096 fasebj 6 6 1347506 PMID 1347506 S2CID 221753076 Rebekah Wang Cheng Joan M Neuner Vanessa M Barnabei 2007 Menopause ACP Press pp 97 ISBN 978 1 930513 83 9 Niels Bergemann Anita Riecher Rossler 27 December 2005 Estrogen Effects in Psychiatric Disorders Springer Science amp Business Media pp 179 ISBN 978 3 211 27063 9 Soderpalm AH Lindsey S Purdy RH Hauger R Wit de H 2004 Administration of progesterone produces mild sedative like effects in men and women Psychoneuroendocrinology 29 3 339 54 doi 10 1016 s0306 4530 03 00033 7 PMID 14644065 S2CID 21796848 de Wit H Schmitt L Purdy R Hauger R 2001 Effects of acute progesterone administration in healthy postmenopausal women and normally cycling women Psychoneuroendocrinology 26 7 697 710 doi 10 1016 s0306 4530 01 00024 5 PMID 11500251 S2CID 20611661 van Broekhoven F Backstrom T Verkes RJ 2006 Oral progesterone decreases saccadic eye velocity and increases sedation in women Psychoneuroendocrinology 31 10 1190 9 doi 10 1016 j psyneuen 2006 08 007 PMID 17034954 S2CID 40466952 Sripada RK Marx CE King AP Rampton JC Ho SS Liberzon I 2013 Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits Biol Psychiatry 73 11 1045 53 doi 10 1016 j biopsych 2012 12 008 PMC 3648625 PMID 23348009 Schmoutz CD Guerin GF Goeders NE 2014 Role of GABA active neurosteroids in the efficacy of metyrapone against cocaine addiction Behav Brain Res 271 269 76 doi 10 1016 j bbr 2014 06 032 PMID 24959859 S2CID 37159095 a b Cohen IV Cirulli ET Mitchell MW Jonsson TJ Yu J Shah N Spector TD Guo L Venter JC Telenti A 2018 Acetaminophen Paracetamol Use Modifies the Sulfation of Sex Hormones EBioMedicine 28 316 323 doi 10 1016 j ebiom 2018 01 033 PMC 5835573 PMID 29398597 Retrieved from https en wikipedia org w index php title Neurosteroidogenesis inhibitor amp oldid 1096303297, wikipedia, wiki, book, books, library,

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