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Neurosteroidogenesis inhibitor

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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] 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,[2][4][10] 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.[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.[1][12][13] 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][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.[11]

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.[22]

See also

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References

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  1. ^ a b c d e f g Reddy DS (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 978-0-444-53630-3. 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. Bibcode:1999PNAS...9613512G. 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. S2CID 21473462.
  8. ^ Griffin LD, Mellon SH (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. doi:10.1073/pnas.96.23.13512. ISSN 0027-8424. PMC 23979. PMID 10557352.
  9. ^ Pinna G, Costa E, Guidotti A (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. doi:10.1007/s00213-005-0213-2. ISSN 0033-3158. PMID 16432684.
  10. ^ 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.
  11. ^ a b Tvrdeić A, Poljak L (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 (inactive 1 November 2024). ISSN 1849-8922.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
  12. ^ 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.
  13. ^ 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.
  14. ^ Paul SM, Purdy RH (1992). "Neuroactive steroids". FASEB J. 6 (6): 2311–22. doi:10.1096/fasebj.6.6.1347506. PMID 1347506. S2CID 221753076.
  15. ^ Rebekah Wang-Cheng, Joan M. Neuner, Vanessa M. Barnabei (2007). Menopause. ACP Press. pp. 97–. ISBN 978-1-930513-83-9.
  16. ^ 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.
  17. ^ 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.
  18. ^ 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.
  19. ^ 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.
  20. ^ 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.
  21. ^ 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.
  22. ^ 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.
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