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Neurochemical Research

, Volume 41, Issue 9, pp 2233–2242 | Cite as

18β-Glycyrrhetinic Acid, a Novel Naturally Derived Agent, Suppresses Prolactin Hyperactivity and Reduces Antipsychotic-Induced Hyperprolactinemia in In Vitro and In Vivo Models

  • Di Wang
  • Yongfeng Zhang
  • Chunyue Wang
  • Dongxu Jia
  • Guangsheng Cai
  • Jiahui Lu
  • Di WangEmail author
  • Zhang-Jin ZhangEmail author
Original Paper

Abstract

The purpose of this study was to examine the effects of 18β-glycyrrhetinic acid (GA), a novel naturally derived agent, in suppressing prolactin (PRL) hyperactivity and reducing antipsychotic-induced hyperprolactinemia (hyperPRL) and the underlying mechanisms in in vitro and in vivo models. GA treatment for 24 h inhibited PRL synthesis and secretion in MMQ cells and cultured pituitary cells in a dose-dependent fashion; but this effect was not reproduced in GH3 cells that lack the expression of functional dopamine D2 receptors. GA suppressed elevated PRL level and growth hormone, and normalized several sex hormones in a rat model of hyperPRL, produced by repeated injection of the dopamine blocker metoclopramide. GA also modulated the expression 5-HT1A and 5-HT2A receptors in both in vivo and in vitro models. These results indicate that GA is effective in suppressing PRL hyperactivity caused by the blockade of dopamine D2 receptors. This suppressive effect of GA may be related to its modulation of the serotonergic system. This study provides additional evidence in support of GA as an adjunct for the treatment of hyperPRL.

Keywords

Hyperprolactinemia Serotonergic system Hormones 18β-Glycyrrhetinic acid 

Abbreviations

GA

18β-Glycyrrhetinic acid

PRL

Prolactin

hyperPRL

Hyperprolactinemia

BMT

Bromocriptine

5-HT

Serotonin

PRFs

Prolactin-releasing factors

VIP

Oxytocin and vasoactive intestinal peptide

GABA

Forebrain γ-aminobutyric acid

TIDA

Tuberoinfundibular dopaminergic

MCP

Metoclopramide

E2

Estradiol

T

Testosterone

P

Progesterone

FSH

Follicle-stimulating hormone

LH

Luteinizing hormone

GH

Growth hormone

ELISA

Enzyme-linked immunosorbent assays

PMSF

Phenylmethanesulfonyl fluoride

DA

Dopamine

GAPDH

Glyceraldehyde-3-phosphate dehydrogenase

HRP

Horseradish peroxidase

Notes

Acknowledgments

This work was supported by the Natural Science foundation of P. R. China (Grant No. 81402955) and General Research Fund (GRF) of Research Grant Council of HKSAR (Grant No. 785813).

Compliance with Ethical Standards

Conflicts of interest

The authors declare no conflict of interest.

Supplementary material

11064_2016_1938_MOESM1_ESM.doc (11.7 mb)
Supplementary material 1 (DOC 11985 kb)

References

  1. 1.
    Bridges RS, DiBiase R, Loundes DD, Doherty PC (1985) Prolactin stimulation of maternal behavior in female rats. Science 227(4688):782–784CrossRefPubMedGoogle Scholar
  2. 2.
    Bridges RS, Ronsheim PM (1990) Prolactin (PRL) regulation of maternal behavior in rats: bromocriptine treatment delays and PRL promotes the rapid onset of behavior. Endocrinology 126(2):837–848. doi: 10.1210/endo-126-2-837 CrossRefPubMedGoogle Scholar
  3. 3.
    Halbreich U, Kahn LS (2003) Hyperprolactinemia and schizophrenia: mechanisms and clinical aspects. J Psychiatr Pract 9(5):344–353CrossRefPubMedGoogle Scholar
  4. 4.
    Gala RR, Shevach EM (1994) Evidence for the release of a prolactin-like substance by mouse lymphocytes and macrophages. Proc Soc Exp Biol Med Soc Exp Biol Med 205(1):12–19CrossRefGoogle Scholar
  5. 5.
    Fitzgerald P, Dinan TG (2008) Prolactin and dopamine: what is the connection? review article. J Psychopharmacol 22(2 Suppl):12–19. doi: 10.1177/0269216307087148 CrossRefPubMedGoogle Scholar
  6. 6.
    Biller BM, Luciano A, Crosignani PG, Molitch M, Olive D, Rebar R, Sanfilippo J, Webster J, Zacur H (1999) Guidelines for the diagnosis and treatment of hyperprolactinemia. J Reprod Med 44(12 Suppl):1075–1084PubMedGoogle Scholar
  7. 7.
    Sun CL, Geng CA, Yin XJ, Huang XY, Chen JJ (2015) Natural products as antidepressants documented in Chinese patents from 1992 to 2013. J Asian Nat Prod Res 17(2):188–198. doi: 10.1080/10286020.2014.985770 CrossRefPubMedGoogle Scholar
  8. 8.
    Wang X, Zhang H, Chen L, Shan L, Fan G, Gao X (2013) Liquorice, a unique “guide drug” of traditional Chinese medicine: a review of its role in drug interactions. J Ethnopharmacol 150(3):781–790. doi: 10.1016/j.jep.2013.09.055 CrossRefPubMedGoogle Scholar
  9. 9.
    Hasan SK, Khan R, Ali N, Khan AQ, Rehman MU, Tahir M, Lateef A, Nafees S, Mehdi SJ, Rashid S, Shahid A, Sultana S (2015) 18-beta Glycyrrhetinic acid alleviates 2-acetylaminofluorene-induced hepatotoxicity in Wistar rats: role in hyperproliferation, inflammation and oxidative stress. Hum Exp Toxicol 34(6):628–641. doi: 10.1177/0960327114554045 CrossRefPubMedGoogle Scholar
  10. 10.
    Wu X, Zhang L, Gurley E, Studer E, Shang J, Wang T, Wang C, Yan M, Jiang Z, Hylemon PB, Sanyal AJ, Pandak WM Jr, Zhou H (2008) Prevention of free fatty acid-induced hepatic lipotoxicity by 18beta-glycyrrhetinic acid through lysosomal and mitochondrial pathways. Hepatology 47(6):1905–1915. doi: 10.1002/hep.22239 CrossRefPubMedGoogle Scholar
  11. 11.
    Mahmoud AM, Al Dera HS (2015) 18beta-Glycyrrhetinic acid exerts protective effects against cyclophosphamide-induced hepatotoxicity: potential role of PPARgamma and Nrf2 upregulation. Genes Nutr 10(6):41. doi: 10.1007/s12263-015-0491-1 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kong SZ, Chen HM, Yu XT, Zhang X, Feng XX, Kang XH, Li WJ, Huang N, Luo H, Su ZR (2015) The protective effect of 18beta-Glycyrrhetinic acid against UV irradiation induced photoaging in mice. Exp Gerontol 61:147–155. doi: 10.1016/j.exger.2014.12.008 CrossRefPubMedGoogle Scholar
  13. 13.
    Wang D, Wong HK, Feng YB, Zhang ZJ (2014) 18beta-glycyrrhetinic acid induces apoptosis in pituitary adenoma cells via ROS/MAPKs-mediated pathway. J Neurooncol 116(2):221–230. doi: 10.1007/s11060-013-1292-2 CrossRefPubMedGoogle Scholar
  14. 14.
    Wang D, Wong HK, Zhang L, McAlonan GM, Wang XM, Sze SC, Feng YB, Zhang ZJ (2012) Not only dopamine D2 receptors involved in peony-glycyrrhiza decoction, an herbal preparation against antipsychotic-associated hyperprolactinemia. Prog Neuropsychopharmacol Biol Psychiatry 39(2):332–338. doi: 10.1016/j.pnpbp.2012.07.005 CrossRefPubMedGoogle Scholar
  15. 15.
    Jorgensen HS (2007) Studies on the neuroendocrine role of serotonin. Dan Med Bull 54(4):266–288PubMedGoogle Scholar
  16. 16.
    Debeljuk L, Lasaga M (2006) Tachykinins and the control of prolactin secretion. Peptides 27(11):3007–3019. doi: 10.1016/j.peptides.2006.07.010 CrossRefPubMedGoogle Scholar
  17. 17.
    Khodr CE, Clark S, Bokov AF, Richardson A, Strong R, Hurley DL, Phelps CJ (2010) Early postnatal administration of growth hormone increases tuberoinfundibular dopaminergic neuron numbers in Ames dwarf mice. Endocrinology 151(7):3277–3285. doi: 10.1210/en.2009-1482 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Oosterhof CA, El Mansari M, Blier P (2014) Acute effects of brexpiprazole on serotonin, dopamine, and norepinephrine systems: an in vivo electrophysiologic characterization. J Pharmacol Exp Ther 351(3):585–595. doi: 10.1124/jpet.114.218578 CrossRefPubMedGoogle Scholar
  19. 19.
    Arnhold IJ, Lofrano-Porto A, Latronico AC (2009) Inactivating mutations of luteinizing hormone beta-subunit or luteinizing hormone receptor cause oligo-amenorrhea and infertility in women. Horm Res 71(2):75–82. doi: 10.1159/000183895 CrossRefPubMedGoogle Scholar
  20. 20.
    Wang D, Wang W, Zhou Y, Wang J, Jia D, Wong HK, Zhang ZJ (2015) Studies on the regulatory effect of Peony-Glycyrrhiza Decoction on prolactin hyperactivity and underlying mechanism in hyperprolactinemia rat model. Neurosci Lett 606:60–65. doi: 10.1016/j.neulet.2015.08.024 CrossRefPubMedGoogle Scholar
  21. 21.
    Ribeiro AB, Leite CM, Kalil B, Franci CR, Anselmo-Franci JA, Szawka RE (2015) Kisspeptin regulates tuberoinfundibular dopaminergic neurones and prolactin secretion in an oestradiol-dependent manner in male and female rats. J Neuroendocrinol 27(2):88–99. doi: 10.1111/jne.12242 CrossRefPubMedGoogle Scholar
  22. 22.
    Nakano M, Minagawa A, Hasunuma I, Okada R, Tonon MC, Vaudry H, Yamamoto K, Kikuyama S, Machida T, Kobayashi T (2010) D2 Dopamine receptor subtype mediates the inhibitory effect of dopamine on TRH-induced prolactin release from the bullfrog pituitary. Gen Comp Endocrinol 168(2):287–292. doi: 10.1016/j.ygcen.2010.05.008 CrossRefPubMedGoogle Scholar
  23. 23.
    Lychkovq AE, Puzikov AM (2014) Prolactin and serotonin. Vestnik Rossiiskoi akademii meditsinskikh nauk/Rossiiskaia akademiia meditsinskikh nauk 1–2:38–45CrossRefPubMedGoogle Scholar
  24. 24.
    Le Tissier PR, Hodson DJ, Martin AO, Romano N, Mollard P (2015) Plasticity of the prolactin (PRL) axis: mechanisms underlying regulation of output in female mice. Adv Exp Med Biol 846:139–162. doi: 10.1007/978-3-319-12114-7_6 CrossRefPubMedGoogle Scholar
  25. 25.
    Lacau-Mengido IM, Libertun C, Becu-Villalobos D (1996) Different serotonin receptor types participate in 5-hydroxytryptophan-induced gonadotropins and prolactin release in the female infantile rat. Neuroendocrinology 63(5):415–421CrossRefPubMedGoogle Scholar
  26. 26.
    Meert TF, Melis W, Aerts N, Clincke G (1997) Antagonism of meta-chlorophenylpiperazine-induced inhibition of exploratory activity in an emergence procedure, the open field test, in rats. Behav Pharmacol 8(4):353–363CrossRefPubMedGoogle Scholar
  27. 27.
    Chaiseha Y, Kang SW, Leclerc B, Kosonsiriluk S, Sartsoongnoen N, El Halawani ME (2010) Serotonin receptor subtypes influence prolactin secretion in the Turkey. Gen Comp Endocrinol 165(1):170–175. doi: 10.1016/j.ygcen.2009.06.018 CrossRefPubMedGoogle Scholar
  28. 28.
    Bakken T, Kang SW, Kosonsiriluk S, Kuwayama T, Chaiseha Y, El Halawani ME (2014) Differential roles of hypothalamic serotonin receptor subtypes in the regulation of prolactin secretion in the turkey hen. Acta Histochem 116(1):131–137. doi: 10.1016/j.acthis.2013.06.002 CrossRefPubMedGoogle Scholar
  29. 29.
    Kapur S, Remington G (1996) Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry 153(4):466–476. doi: 10.1176/ajp.153.4.466 CrossRefPubMedGoogle Scholar
  30. 30.
    Lucas G, De Deurwaerdere P, Porras G, Spampinato U (2000) Endogenous serotonin enhances the release of dopamine in the striatum only when nigro-striatal dopaminergic transmission is activated. Neuropharmacology 39(11):1984–1995CrossRefPubMedGoogle Scholar
  31. 31.
    Bortolozzi A, Diaz-Mataix L, Scorza MC, Celada P, Artigas F (2005) The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity. J Neurochem 95(6):1597–1607. doi: 10.1111/j.1471-4159.2005.03485.x CrossRefPubMedGoogle Scholar
  32. 32.
    Dupre KB, Eskow KL, Negron G, Bishop C (2007) The differential effects of 5-HT(1A) receptor stimulation on dopamine receptor-mediated abnormal involuntary movements and rotations in the primed hemiparkinsonian rat. Brain Res 1158:135–143. doi: 10.1016/j.brainres.2007.05.005 CrossRefPubMedGoogle Scholar
  33. 33.
    Halbreich U, Kinon BJ, Gilmore JA, Kahn LS (2003) Elevated prolactin levels in patients with schizophrenia: mechanisms and related adverse effects. Psychoneuroendocrinology 28(Suppl 1):53–67CrossRefPubMedGoogle Scholar
  34. 34.
    Sakamoto K, Wakabayashi K (1988) Inhibitory effect of glycyrrhetinic acid on testosterone production in rat gonads. Endocrinologia Japonica 35(2):333–342CrossRefPubMedGoogle Scholar
  35. 35.
    Whorwood CB, Sheppard MC, Stewart PM (1993) Licorice inhibits 11 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid levels and potentiates glucocorticoid hormone action. Endocrinology 132(6):2287–2292. doi: 10.1210/endo.132.6.8504732 PubMedGoogle Scholar
  36. 36.
    Armanini D, Mattarello MJ, Fiore C, Bonanni G, Scaroni C, Sartorato P, Palermo M (2004) Licorice reduces serum testosterone in healthy women. Steroids 69(11–12):763–766. doi: 10.1016/j.steroids.2004.09.005 CrossRefPubMedGoogle Scholar
  37. 37.
    Fukui M, Kitagawa Y, Nakamura N, Kadono M, Mogami S, Hirata C, Ichio N, Wada K, Hasegawa G, Yoshikawa T (2003) Association between serum testosterone concentration and carotid atherosclerosis in men with type 2 diabetes. Diabetes Care 26(6):1869–1873CrossRefPubMedGoogle Scholar
  38. 38.
    Barth C, Villringer A, Sacher J (2015) Sex hormones affect neurotransmitters and shape the adult female brain during hormonal transition periods. Front Neurosci 9:37. doi: 10.3389/fnins.2015.00037 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Michopoulos V, Berga SL, Wilson ME (2011) Estradiol and progesterone modify the effects of the serotonin reuptake transporter polymorphism on serotonergic responsivity to citalopram. Exp Clin Psychopharmacol 19(6):401–408. doi: 10.1037/a0025008 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Di Wang
    • 1
  • Yongfeng Zhang
    • 1
  • Chunyue Wang
    • 1
  • Dongxu Jia
    • 1
  • Guangsheng Cai
    • 1
  • Jiahui Lu
    • 1
  • Di Wang
    • 1
    Email author
  • Zhang-Jin Zhang
    • 2
    Email author
  1. 1.School of Life SciencesJilin UniversityChangchunChina
  2. 2.School of Chinese MedicineThe University of Hong KongHong KongChina

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