Neurosteroidogenesis inhibitor explained

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). 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.[5] [6] [7] Some SSRI antidepressants, such as fluoxetine, sertraline, and paroxetine, have been observed to exert this effect at concentrations that are inactive on serotonin reuptake.[8] [9] Inhibition of inhibitory neurosteroid biosynthesis by 5α-reductase inhibitors and 3α-HSD inhibitors has been associated with depression, anxiety, irritability, and sexual dysfunction,[10] whereas enhancement of their biosynthesis has been implicated in the antidepressant and anxiolytic effects of some of the SSRIs.

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.[11] 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.[12] [13] It is activated by certain benzodiazepines such as diazepam and midazolam, and via this action, inhibitory neurosteroid levels are increased. Selective TSPO activators, such as emapunil, are under investigation for clinical use as possible anxiolytics.

Progesterone, which is the endogenous precursor to the inhibitory neurosteroids 5α-dihydroprogesterone and allopregnanolone, as well as, more distantly, THDOC,[14] when administered exogenously, has been found to behave as a prodrug to these neurosteroids,[15] [16] with clinical signs of their action, such as sedation, readily evident in humans.[17] [18] [19] Exogenous pregnenolone has similarly been found to act as a prodrug of allopregnanolone.[20]

Metyrapone, a reversible inhibitor of the enzyme steroid 11β-hydroxylase, may increase inhibitory neurosteroid levels.[21] Conversely, it may inhibit the production of cortisol-derived excitatory neurosteroids.

Paracetamol (acetaminophen; Tylenol) has been shown to act at SULT2A1 (and potentially at SULT2B1) as an inhibitor of neurosteroidogenesis.[22] Specifically, the production of sulfate-containing neurosteroids, such as DHEA-S and pregnenolone sulfate, were decreased in patients taking paracetamol.

See also

Notes and References

  1. Book: Reddy. Doodipala Samba. Sex Differences in the Human Brain, their Underpinnings and Implications. Neurosteroids. 186. 2010. 113–137. 0079-6123. 10.1016/B978-0-444-53630-3.00008-7. 21094889. 3139029. Progress in Brain Research. 978-0-444-53630-3.
  2. Traish AM, Mulgaonkar A, Giordano N . The dark side of 5α-reductase inhibitors' therapy: sexual dysfunction, high Gleason grade prostate cancer and depression . Korean J Urol . 55 . 6 . 367–79 . June 2014 . 24955220 . 10.4111/kju.2014.55.6.367 . 4064044.
  3. Meyer L, Venard C, Schaeffer V, Patte-Mensah C, Mensah-Nyagan AG . 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 . April 2008 . 18291663 . 10.1016/j.nbd.2007.12.001 . 5830825 .
  4. Pazol K, Wilson ME, Wallen K . Medroxyprogesterone acetate antagonizes the effects of estrogen treatment on social and sexual behavior in female macaques . J. Clin. Endocrinol. Metab. . 89 . 6 . 2998–3006 . June 2004 . 15181090 . 1440328 . 10.1210/jc.2003-032086 .
  5. Griffin LD, Mellon SH . Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes . Proc. Natl. Acad. Sci. U.S.A. . 96 . 23 . 13512–7 . November 1999 . 10557352 . 23979 . 10.1073/pnas.96.23.13512 . 1999PNAS...9613512G . free .
  6. Pinna G . 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 . September 2010 . 20716970 . 2942072 . 10.1097/FBP.0b013e32833d8ba0 .
  7. Schüle C, Romeo E, Uzunov DP, Eser D, di Michele F, Baghai TC, Pasini A, Schwarz M, Kempter H, Rupprecht R . Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha-hydroxysteroid dehydrogenase activity . Mol. Psychiatry . 11 . 3 . 261–72 . March 2006 . 16344854 . 10.1038/sj.mp.4001782 . 21473462 .
  8. Griffin . Lisa D. . Mellon . Synthia H. . 1999-11-09 . Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes . Proceedings of the National Academy of Sciences of the United States of America . 96 . 23 . 13512–13517 . 0027-8424 . 10557352.
  9. Pinna . Graziano . Costa . Erminio . Guidotti . Alessandro . June 2006 . Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake . Psychopharmacology . 186 . 3 . 362–372 . 10.1007/s00213-005-0213-2 . 0033-3158 . 16432684.
  10. Civic D, Scholes D, Ichikawa L, etal . Depressive symptoms in users and non-users of depot medroxyprogesterone acetate . Contraception . 61 . 6 . 385–90 . June 2000 . 10958882 . 10.1016/s0010-7824(00)00122-0.
  11. Tvrdeić. Ante. Poljak. Ljiljana. Neurosteroids, GABAA receptors and neurosteroid based drugs: are we witnessing the dawn of the new psychiatric drugs?. Endocrine Oncology and Metabolism. 2. 1. 2016. 60–71. 1849-8922. 10.21040/eom/2016.2.7. 2024-04-06 . free.
  12. Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapère JJ, Lindemann P, Norenberg MD, Nutt D, Weizman A, Zhang MR, Gavish M . 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 . August 2006 . 16822554 . 10.1016/j.tips.2006.06.005 .
  13. Dhir A, Rogawski MA . Role of neurosteroids in the anticonvulsant activity of midazolam . British Journal of Pharmacology . 165 . 8 . 2684–91 . Apr 2012 . 22014182 . 3423249 . 10.1111/j.1476-5381.2011.01733.x .
  14. Paul SM, Purdy RH . Neuroactive steroids . FASEB J. . 6 . 6 . 2311–22 . 1992 . 1347506 . 10.1096/fasebj.6.6.1347506. 221753076 . free .
  15. Book: Rebekah Wang-Cheng. Joan M. Neuner. Vanessa M. Barnabei. Menopause. 2007. ACP Press. 978-1-930513-83-9. 97–.
  16. Book: Niels Bergemann. Anita Riecher-Rössler. Estrogen Effects in Psychiatric Disorders. 27 December 2005. Springer Science & Business Media. 978-3-211-27063-9. 179–.
  17. Söderpalm AH, Lindsey S, Purdy RH, Hauger R, Wit de H . Administration of progesterone produces mild sedative-like effects in men and women . Psychoneuroendocrinology . 29 . 3 . 339–54 . 2004 . 14644065 . 10.1016/s0306-4530(03)00033-7. 21796848 .
  18. de Wit H, Schmitt L, Purdy R, Hauger R . Effects of acute progesterone administration in healthy postmenopausal women and normally-cycling women . Psychoneuroendocrinology . 26 . 7 . 697–710 . 2001 . 11500251 . 10.1016/s0306-4530(01)00024-5. 20611661 .
  19. van Broekhoven F, Bäckström T, Verkes RJ . Oral progesterone decreases saccadic eye velocity and increases sedation in women . Psychoneuroendocrinology . 31 . 10 . 1190–9 . 2006 . 17034954 . 10.1016/j.psyneuen.2006.08.007 . 40466952 .
  20. Sripada RK, Marx CE, King AP, Rampton JC, Ho SS, Liberzon I . Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits . Biol. Psychiatry . 73 . 11 . 1045–53 . 2013 . 23348009 . 3648625 . 10.1016/j.biopsych.2012.12.008 .
  21. Schmoutz CD, Guerin GF, Goeders NE . Role of GABA-active neurosteroids in the efficacy of metyrapone against cocaine addiction . Behav. Brain Res. . 271 . 269–76 . 2014 . 24959859 . 10.1016/j.bbr.2014.06.032 . 37159095 .
  22. Cohen IV, Cirulli ET, Mitchell MW, Jonsson TJ, Yu J, Shah N, Spector TD, Guo L, Venter JC, Telenti A . Acetaminophen (Paracetamol) Use Modifies the Sulfation of Sex Hormones . eBioMedicine . 28. 316–323. 2018 . 29398597 . 5835573 . 10.1016/j.ebiom.2018.01.033 .

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