Chemistry: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] 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. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Reddy, Doodipala Samba (2010). "Neurosteroids". Sex Differences in the Human Brain, their Underpinnings and Implications. Progress in Brain Research. 186. pp. 113–137. doi:10.1016/B978-0-444-53630-3.00008-7. ISBN 9780444536303. 
  2. ↑ 2.0 2.1 "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. doi:10.4111/kju.2014.55.6.367. PMID 24955220. 
  3. ↑ "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. doi:10.1016/j.nbd.2007.12.001. PMID 18291663. 
  4. ↑ 4.0 4.1 "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. doi:10.1210/jc.2003-032086. PMID 15181090. 
  5. ↑ "Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes". Proc. Natl. Acad. Sci. U.S.A. 96 (23): 13512–7. November 1999. doi:10.1073/pnas.96.23.13512. PMID 10557352. Bibcode: 1999PNAS...9613512G. 
  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. PMID 20716970. 
  7. ↑ "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. doi:10.1038/sj.mp.4001782. PMID 16344854. 
  8. ↑ "Depressive symptoms in users and non-users of depot medroxyprogesterone acetate". Contraception 61 (6): 385–90. June 2000. doi:10.1016/s0010-7824(00)00122-0. PMID 10958882. 
  9. ↑ 9.0 9.1 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. ↑ 10.0 10.1 "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. doi:10.1016/j.tips.2006.06.005. PMID 16822554. 
  11. ↑ 11.0 11.1 "Role of neurosteroids in the anticonvulsant activity of midazolam". British Journal of Pharmacology 165 (8): 2684–91. Apr 2012. doi:10.1111/j.1476-5381.2011.01733.x. PMID 22014182. 
  12. ↑ "Neuroactive steroids". FASEB J. 6 (6): 2311–22. 1992. doi:10.1096/fasebj.6.6.1347506. PMID 1347506. 
  13. ↑ Rebekah Wang-Cheng; Joan M. Neuner; Vanessa M. Barnabei (2007). Menopause. ACP Press. pp. 97–. ISBN 978-1-930513-83-9. https://books.google.com/books?id=mPs5Ly71OCQC&pg=PA97. 
  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. https://books.google.com/books?id=L4YQ50SbBnsC&pg=PA179. 
  15. ↑ "Administration of progesterone produces mild sedative-like effects in men and women". Psychoneuroendocrinology 29 (3): 339–54. 2004. doi:10.1016/s0306-4530(03)00033-7. PMID 14644065. 
  16. ↑ "Effects of acute progesterone administration in healthy postmenopausal women and normally-cycling women". Psychoneuroendocrinology 26 (7): 697–710. 2001. doi:10.1016/s0306-4530(01)00024-5. PMID 11500251. 
  17. ↑ "Oral progesterone decreases saccadic eye velocity and increases sedation in women". Psychoneuroendocrinology 31 (10): 1190–9. 2006. doi:10.1016/j.psyneuen.2006.08.007. PMID 17034954. 
  18. ↑ "Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits". Biol. Psychiatry 73 (11): 1045–53. 2013. doi:10.1016/j.biopsych.2012.12.008. PMID 23348009. 
  19. ↑ "Role of GABA-active neurosteroids in the efficacy of metyrapone against cocaine addiction". Behav. Brain Res. 271: 269–76. 2014. doi:10.1016/j.bbr.2014.06.032. PMID 24959859. 
  20. ↑ 20.0 20.1 "Acetaminophen (Paracetamol) Use Modifies the Sulfation of Sex Hormones". eBioMedicine 28: 316–323. 2018. doi:10.1016/j.ebiom.2018.01.033. PMID 29398597. 



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