Neurosteroidogenesis inhibitor

A neurosteroidogenesis inhibitor is a drug that inhibits the endogenous production of 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]

Inhibitory neurosteroids are biosynthesized 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 by certain selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, fluvoxamine, sertraline, and paroxetine, as well as 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 all neurosteroids, both excitatory and inhibitory, while inhibitors of 17α-hydroxylase and 17,20-lyase, such as abiraterone acetate, may block production of excitatory neurosteroids.[9] Antigonadotropins may also lower 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]

Metyrapone, a reversible inhibitor of the enzyme steroid 11β-hydroxylase, may increase inhibitory neurosteroid levels.[18] Contrarily, it may inhibit the production of cortisol-derived excitatory neurosteroids.[9]

See also

References

  1. 1 2 3 4 5 6 7 Reddy, Doodipala Samba (2010). "Neurosteroids". Progress in Brain Research. 186: 113–137. doi:10.1016/B978-0-444-53630-3.00008-7. ISSN 0079-6123. PMC 3139029Freely accessible. PMID 21094889.
  2. 1 2 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 4064044Freely accessible. 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.
  4. 1 2 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 1440328Freely accessible. 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 23979Freely accessible. 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 2942072Freely accessible. 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. 1 2 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. 1 2 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. 1 2 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 3423249Freely accessible. PMID 22014182.
  12. ↑ Paul SM, Purdy RH (1992). "Neuroactive steroids". FASEB J. 6 (6): 2311–22. PMID 1347506.
  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.
  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.
  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.
  18. ↑ 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.
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