Inhibitory effects of thymoquinone on hypothalamic aromatase and ghrelin gene expression in intact and diabetic rats

Document Type : Research Paper

Authors

Department of Biology, Faculty of Science, University of Mohaghegh Ardabili, Ardabil, Iran

Abstract

Background and Objective: Thymoquinone stimulates the activity of hypothalamic-pituitary-gonadal axis (HPG). Diabetes, ghrelin and aromatase are associated with decreased function of HPG axis. This study aimed to investigate the influence of thymoquinone on aromatase and ghrelin gene expression in intact and diabetic rats.
Materials and Methods: Twenty male Wistar rats weighing 190-220 g were used. Diabetes type 1 was induced by alloxan. Saline or thymoquinone (10 mg/kg) was injected into intact or diabetic rats intraperitoneally for two weeks. One day after last injection, the hypothalamic samples were removed. Relative gene expression of aromatase and ghrelin was determined by RT-PCR method.
Results: Thymoquinone did not alter the aromatase expressions in the healthy rats. However, it caused a marked decrease in ghrelin expression in healthy rats. The aromatase and ghrelin expression significantly reduced in the diabetic rats receiving thymoquinone in comparison with diabetic group.
Conclusion: Thymoquinone may be a drug to improve decreased HPG axis activity of diabetic rats due to its inhibitory effects on aromatase and ghrelin upstream GnRH neurons.

Keywords


  1. Shpakov AO. The role of disturbances in hormonal signaling systems in etiology and pathogenesis of diabetes mellitus. Journal of Evolutionary Biochemistry and Physiology 2014;50(6):552-6.
  2. Gargouri M, Magné C, El Feki A. Hyperglycemia, oxidative stress, liver damage and dysfunction in alloxan-induced diabetic rat are prevented by Spirulina supplementation. Nutrition research 2016;36(11):1255-68.
  3. Schoeller EL, Schon S, Moley KH. The effects of type 1 diabetes on the hypothalamic, pituitary and testes axis. Cell and Tissue Research 2012;349(3):839-47.
  4. Roselli CF. Brain aromatase: roles in reproduction and neuroprotection. The Journal of Steroid Biochemistry and Molecular Biology 2007;106(1-5):143-50.
  5. Carreau S, Wolczynski S, Galeraud-Denis I. Aromatase, oestrogens and human male reproduction. Philosophical Transactions of the Royal Society B: Biological Sciences 2010 27;365(1546):1571-9.
  6. Haghighat gollo Kh, Mahmoudi F, Bayrami A, Zahri S. Influences of l-dopa and blocking dopamine receptors on aromatase gene expression and serum concentration of lh in rat model of polycystic ovary syndrome. Journal of Fasa University of Medical Sciences 2020;10(3):2448-55.
  7. Ghanim H, Dhindsa S, Abuaysheh S, Batra M, Kuhadiya ND, Makdissi A, Chaudhuri A, Dandona P. Diminished androgen and estrogen receptors and aromatase levels in hypogonadal diabetic men: reversal with testosterone. European Journal of Endocrinology 2018 ;178(3):277-83.
  8. Atta MS, Almadaly EA, El-Far AH, Saleh RM, Assar DH, Al Jaouni SK, Mousa SA. Thymoquinone defeats diabetes-induced testicular damage in rats targeting antioxidant, inflammatory and aromatase expression. International Journal of Molecular Sciences 2017; 18(5):919.
  9. Burul-Bozkurt N, Pekiner C, Kelicen P. Diabetes alters aromatase enzyme levels in gonadal tissues of rats. Naunyn-Schmiedeberg's Archives of Pharmacology 2010;382(1):33-41.
  10. Banks KA, Murphy KG. Role of ghrelin in glucose homeostasis and diabetes. Diabetes Management 2013;3(2):171.
  11. Farkas I, Vastagh C, Sárvári M, Liposits Z. Ghrelin decreases firing activity of gonadotropin-releasing hormone (GnRH) neurons in an estrous cycle and endocannabinoid signaling dependent manner. PLoS One 2013;8(10):e78178.
  12. Parandin R, Yousofvand N, Ghorbani R. The enhancing effects of alcoholic extract of Nigella sativa seed on fertility potential, plasma gonadotropins and testosterone in male rats. Iranian Journal of Reproductive Medicine 2012;10(4):355.
  13. Kanter M. Thymoquinone reestablishes spermatogenesis after testicular injury caused by chronic toluene exposure in rats. Toxicology and Industrial Health 2011;27(2):155-66.
  14. Attari SS, Mohammadi S, Ebrahimzadeh A, Hosseinzadeh H, Soukhtanloo M, Rajabzadeh A. Effects of thymoquinone on sperm parameters, apoptosis, testosterone level, and oxidative stress in a mouse model of D-galactose-induced aging. Pharmaceutical Sciences 2018;24(3):180-6.
  15. Salahshoor MR, Haghjoo M, Roshankhah S, Makalani F, Jalili C. Effect of thymoquinone on reproductive parameter in morphine-treated male mice. Advanced Biomedical Research 2018;7:18.
  16. Mahmoudi F, Mahmoudi F, Gollo KH, Amini MM. Biosynthesis of novel silver nanoparticles using Eryngium thyrsoideum Boiss extract and comparison of their antidiabetic activity with chemical synthesized silver nanoparticles in diabetic rats. Biological Trace Element Research 2021;199(5):1967-78.
  17. Azcoitia I, Mendez P, Garcia-Segura LM. Aromatase in the Human Brain. Androgens: Clinical Research and Therapeutics 2021;2(1):189-202.
  18. Aloisi AM, Ceccarelli I, Fiorenzani P, Maddalena M, Rossi A, Tomei V, Sorda G, Danielli B, Rovini M, Cappelli A, Anzini M. Aromatase and 5-alpha reductase gene expression: modulation by pain and morphine treatment in male rats. Molecular Pain 2010;6:1744-8069.
  19. Khazali H, Mahmoudi F. Morphine and kisspeptin influences on 5-α reductase and aromatase gene expression in adult male rats. Iranian Journal of Basic Medical Sciences2019;22(12):1462.
  20. Shen M, Shi H. Sex hormones and their receptors regulate liver energy homeostasis. International Journal of Endocrinology 2015;2015.
  21. Ishii S, Kamegai J, Tamura H, Shimizu T, Sugihara H, Oikawa S. Role of ghrelin in streptozotocin-induced diabetic hyperphagia. Endocrinology 2002;143(12):4934-7.
  22. Dong J, Peeters TL, De Smet B, Moechars D, Delporte C, Vanden Berghe P, Coulie B, Tang M, Depoortere I. Role of endogenous ghrelin in the hyperphagia of mice with streptozotocin-induced diabetes. Endocrinology 2006;147(6):2634-42.
  23. Gelling RW, Overduin J, Morrison CD, Morton GJ, Frayo RS, Cummings DE, Schwartz MW. Effect of uncontrolled diabetes on plasma ghrelin concentrations and ghrelin-induced feeding. Endocrinology 2004;145(10):4575-82.
  24. Sönmez MF, Karabulut D, Kilic E, Akalin H, Sakalar C, Gunduz Y, Kara A, Dundar M. The effects of streptozotocin-induced diabetes on ghrelin expression in rat testis: biochemical and immunohistochemical study. Folia Histochemica et Cytobiologica 2015;53(1):26-34.
  25. Hamdy NM, Taha RA. Effects of Nigella sativa oil and thymoquinone on oxidative stress and neuropathy in streptozotocin-induced diabetic rats. Pharmacology 2009;84(3):127-34.
  26. Walters JM, Ward GM, Barton J, Arackal R, Boston RC, Best JD, Alford FP. The effect of norepinephrine on insulin secretion and glucose effectiveness in non—insulin-dependent diabetes. Metabolism 1997;46(12):1448-53.
  27. Gagnon J, Anini Y. Insulin and norepinephrine regulate ghrelin secretion from a rat primary stomach cell culture. Endocrinology 2012;153(8):3646-56.
  28. Chabot F, Caron A, Laplante M, St-Pierre DH. Interrelationships between ghrelin, insulin and glucose homeostasis: Physiological relevance. World Journal of Diabetes 2014;5(3):328.
  29. Ueno M, Carvalheira JB, Oliveira RL, Velloso LA, Saad MJ. Circulating ghrelin concentrations are lowered by intracerebroventricular insulin. Diabetologia 2006; 49(10):2449-52.