Role of Ovarian Hormones in Psychological Stress-induced Oxidative Organ Damage in Rats

Year 2016, Volume: 6 Issue: 2, 72 - 79, 27.10.2016

Gülsün Memi Berrak Ç. Yeğen

Abstract

Objective: Stress response varies with respect to gender via the hypothalamic–pituitary–gonadal axis. We aimed to investigate the effect of ovarian hormone deficiency on psychological stress response and oxidative damage.

 

Methods: Female Sprague Dawley rats (250–300 g, n=56) were divided as control, sham, and ovariectomy (OVX) groups. Sham operation or surgical OVX were conducted under anesthesia. After 60 days, the rats were placed in a special chamber to induce psychological stress by electric shock and were kept in the same chamber for 30 min on the following 3 days. Glucocorticoid receptor antagonist RU-486 (10 mg/kg), oxytocin receptor antagonist atosiban (1 mg/kg), or saline was intraperitoneally administered 10 min before stress exposure. After the hole-board anxiety test, the rats were decapitated on the 4th day; tissue and blood samples were obtained.

 

Results: Psychological stress increased cortisol levels in the RU-486-administered group, while cortisol levels were decreased in the atosiban-administered group. Serum interleukin (IL)-1β levels, but not TNF-α levels, were increased by inducing stress. Stress increased oxidative damage in the stomach, colon, and brain of ovariectomized rats (p<0.05–0.001), while atosiban partially reversed and RU-486 exaggerated oxidative damage. GSH levels that were depleted because of stress were partially replenished by administering atosiban; however, RU-486 had no effect on GSH levels.

 

Conclusion: Although the absence of ovarian hormones during psychological stress had no effect on cortisol or anxiety levels, changes in cytokine levels and oxidative tissue damage were observed.

Sıçanlarda Psikolojik Strese Bağlı Oksidan Doku Hasarında Over Hormonlarının Rolü

Abstract

Amaç: Hipotalamus-hipofiz-gonad aksının etkisiyle, stres yanıtının cinsiyetler arasında farklılıklar gösterdiği bilinmektedir. Bu çalışmada postmenopozal dönemde over hormonlarının yokluğunun, psikolojik stres yanıtı ve oksidatif hasar üzerindeki rolünün araştırılması amaçlandı.

 

Yöntemler: Dişi Sprague-Dawley sıçanlar (250-300 g, n=56) kontrol, taklit cerrahi ve overektomi (OVX) olarak 3 gruba ayrıldı. Anestezi sonrası taklit cerrahi ve OVX işlemi uygulandı. Cerrahi işlemden 60 gün sonra psikolojik stres oluşturmak üzere sıçanlar elektrik şokunun uygulandığı özel bir bölmeye yerleştirildiler. Ardından 3 gün daha aynı bölmede, aynı süre ile şok uygulanmadan tutuldular. Stres uygulamalarının 10’ar dakika öncesinde sıçanlara intraperitoneal yolla glukokortikoid reseptör antagonisti RU-486 (10 mg/kg) veya oksitosin reseptör antagonisti atosiban (1 mg/kg) veya serum fizyolojik verildi. Dördüncü günde delikli levha testi uygulanmasını takiben sıçanlar dekapite edilerek, doku ve kan örnekleri alındı.

 

Bulgular: Psikolojik stres, RU-486 verilen gruplarda kortizol düzeylerini anlamlı olarak arttırırken atosiban verilen gruplarda azalttı. Stres uygulaması ile serum IL-1β düzeyleri artarken, serum TNF-α düzeylerinde değişiklik gözlenmedi. Stres, özellikle overektomi uygulanmış sıçanlarda mide, kolon ve beyin dokularında oksidatif hasarı arttırırken (p<0,05-0,001), RU-486’nın bu hasarı daha fazla arttırdığı, atosibanın ise bu etkiyi kısmen geri döndürdüğü gözlendi. Stres uygulaması ile azalan doku antioksidan miktarını RU-486 tedavisi değiştirmedi, ama atosiban kısmen arttırdı.

 

Sonuç: Çalışmanın bulguları, psikolojik stres durumunda over hormonlarının yokluğunun kortizol düzeyinde ya da anksiyete düzeyinde değişikliğe neden olmadığı halde, sitokin düzeylerinde ve dokuların oksidatif hasar durumlarında değişikliklere yol açabildiğini ortaya koymuştur.

Keywords

Hipotalamus-hipofiz-adrenal bez aksı, hipotalamus-hipofiz-gonad aksı, glukokortikoid reseptörü, atosiban, oksitosin

References

• Viau V. Functional cross-talk between the hypothalamic-pituitary-go- nadal and -adrenal axes. J Neuroendocrinol 2002; 14: 506-13. [CrossRef]
• Kudielka B M, Kirschbaum C. Sex differences in HPA axis responses to stress: a review. Biol Psychol 2005; 69: 113-32. [CrossRef]
• Handa RJ, Burgess LH, Kerr JE, O’Keefe JA. Gonadal steroid hormone re- ceptors and sex differences in the hypothalamo–pituitary–adrenal axis. Horm Behav 1996; 28: 464-76. [CrossRef]
• Toufexis D, Rivarola MA, Lara H, Viau V. Stress and the Reproductive Axis. J Neuroendocrinol 2014; 26: 573-86. [CrossRef]
• Handa RJ, Weiser MJ. Gonadal steroid hormones and the hypothalamo–pi- tuitary–adrenal axis. Front Neuroendocrinol 2014; 35: 197-220. [CrossRef]
• Kajantie E, Phillips DI. The effects of sex and hormonal status on the physiological response to acute psychosocial stress. Psychoneuroendo- crinology 2006; 31: 151-78. [CrossRef]
• Frey BN, Lord C, Soares CN. Depression during menopausal transition: a review of treatment strategies and pathophysiological correlates. Meno- pause Int 2008; 14: 123-8. [CrossRef]
• Lagunas N, Calmarza-Font I, Diz-Chaves Y, Garcia-Segura LM. Long-term ova- riectomy enhances anxiety and depressive-like behaviors in mice submitted to chronic unpredictable stress. Horm Behav 2010; 58: 786-91. [CrossRef]
• Pradhan AD, Manson JE, Rossouw JE, Siscovick DS, Mouton CP, Wallace RB et al. Hormone replacement therapy, and incident coronary heart dis- ease. JAMA 2002; 288: 980-7. [CrossRef]
• Halcox JPJ, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA et al. Prognostic value of coronary vascular endothelial dysfunction. Cir- culation 2002; 106: 653-8. [CrossRef]
• Steptoe A, Hamer M, Chida Y. The effects of acute psychological stress on circulating inflammatory factors in humans: A review and meta-analysis. Brain Behav Immun 2007; 21: 901-12. [CrossRef]
• Prather AA, Carroll JE, Fury JM, McDade KK, Ross D, Marsland AL. Gender differences in stimulated cytokine production following acute psycho- logical stress. Brain Behav Immun 2009; 23: 622-8. [CrossRef]
• Victorino VJ, Panis C, Campos FC, Cayres RC, Colado-Simão AN, Oliveira SR et al. Decreased oxidant profile and increased antioxidant capacity in nat- urally postmenopausal women. Age (Dordr) 2013; 35: 1411-21. [CrossRef]
• Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function and regulation. Physiol Rev 2001; 81: 629-83.
• Ross HE, Young LJ. Oxytocin and the neural mechanisms regulating so- cial cognition and affiliative behavior. Front Neuroendocrinol 2009; 30: 534-47. [CrossRef]
• Taylor SE, Klein LC, Lewis BP, Gruenewald TL Gurung RA, Updegraff JA. Biobehavioral responses to stress infemales: tend-and-befriend, not fight-or-flight. Psychol Rev 2000; 107: 411-29. [CrossRef]
• Yeğen BÇ. Oxytocin and hypothalamo-pituitaryadrenal axis. Marmara Pharm J 2010; 14: 61-6. [CrossRef]
• Petersson M, Hulting AL, Uvnas-Moberg K. Oxytocin causes a sustained decrease in plasma levels of corticosterone in rats. Neurosci Lett 1999; 264: 41-4. [CrossRef]
• Uvnas-Moberg K. Oxytocin may mediate the benefits of positive social interac- tion and emotions. Psychoneuroendocrinology 1998; 23: 819-35. [CrossRef]
• Uvnas-Moberg K, Ahlenius S, Hillegaart V, Alster P. High doses of oxytocin cause sedation and low doses cause an anxiolytic-like effect in male rats. Pharmacol Biochem Behav 1994; 49: 101-6. [CrossRef]
• Lundeberg T, Uvnas-Moberg K, Agren G, Bruzelius G. Anti-nociceptive ef- fects of oxytocin in rats and mice. Neurosci Lett 1994; 170: 153-7. [CrossRef]
• Düşünceli F, Işeri SO, Ercan F, Gedik N, Yeğen C, Yeğen BC. Oxytocin al- leviates hepatic ischemia-reperfusion injury in rats. Peptides 2008; 29: 1216-22. [CrossRef]
• Işeri SO, Sener G, Saglam B, Gedik N, Ercan F, Yegen BC. Oxytocin protects against sepsis-induced multiple organ damage: role of neutrophils. J Surg Res 2005; 126: 73-81. [CrossRef]
• Gülpinar MA, Ozbeyli D, Arbak S, Yeğen BC. Anti-inflammatory effect of acute stress on experimental colitis is mediated by cholecystokinin-B re- ceptors. Life Sci 2004; 21: 77-91. [CrossRef]
• Cetinel S, Hancioğlu S, Sener E, Uner C, Kiliç M, Sener G, et al. Oxytocin treatment alleviates stress-aggravated colitis by a receptor-dependent mechanism. Regul Pept 2010; 160: 146-52. [CrossRef]
• Maier SF, Watkins LR. Cytokines for psychologists: implications of bidi- rectional immune-to-brain communication for understanding behavior, mood, and cognition. Psycho Rev 1998; 105: 83-107. [CrossRef]
• Kim OY, Chae JS, Paik JK, Seo HS, Jang Y, Cavaillon JM, et al. Effects of ag- ing and menopause on serum interleukin-6 levels and peripheral blood mononuclear cell cytokine production in healthy nonobese women. Age (Dordr) 2012; 34: 415-25. [CrossRef]
• Steptoe A, Owen N, Kunz-Ebrecht S, Mohamed-Ali V. Inflammatory cyto- kines, socioeconomic status, and acute stress responsivity. Brain Behav Immun 2002; 16: 774-84. [CrossRef]
• Prather AA, Carroll JE, Fury JM, McDade KK, Ross D, Marsland AL. Gender differences in stimulated cytokine production following acute psycho- logical stress. Brain Behav Immun 2009; 23: 622-8. [CrossRef]
• Walsh B, Shiff I. Menopause. Becker et al. Principles and Practice of En- docrinology and Metabolism. Philadelphia, PA : Lippincott, Williams & Wilkins. 2001; p. 982-91.
• Liu H, Liu K, Bodenner DL. Estrogen receptor inhibits interleukin-6 gene expression by disruption of nuclear factor kB transactivation. Cytokine 2005; 31: 251-7. [CrossRef]
• Kuriyama H, Shibasaki T. Sexual differentiation of the effects of emotional stress on food intake in rats. Neuroscience 2004; 124: 459-65. [CrossRef]
• Kirschbaum C, Schommer N, Federenko I, Gaab J, Neumann O, Oellers M, et al. Short term estradiol treatment enhances pituitary-adrenal axis and sympathetic response to psychosocial stres in healty young men. J Clin Endocrinol Metab 1996; 81: 3639-43. [CrossRef]
• Hoeksema SN. Gender Differences in Depression. Current Directions in Psychological Science 2002; 10: 173- 6. [CrossRef]
• Yayou K, Ito S, Kasuya E, Sutoh M, Ohkura S, Okamura H. Intracerebro- ventricularly administered oxytocin attenuated cortisol secretion, but not behavioral responses, during isolation in Holstein steers. J Vet Med Sci 2008; 70: 665-71. [CrossRef]
• Lu NZ, Bethea CL. Ovarian steroid regulation of 5-HT1A receptor binding and G protein activation in female monkeys. Neuropsycopharmacology 2002; 27: 12-24. [CrossRef]
• Neumann ID, Tornet L, Wigger A. Brain oxytocin: differential inhibition of neuroendocrine stress and anxiety-related behaviour in virgin, preg- nant, and lactating rats. Neuroscience 2000; 95: 567-75. [CrossRef]
• Windle RJ, Shanks N, Lightman SL, Ingram CD. Central oxytocin admin- istration reduces stress-induced corticosterone release and anxiety be- havior in rats. Endocrinology 1997; 138: 2829-34. [CrossRef]
• Parker KJ, Buckmaster CL, Schatzberg AF, Lyons DM. Intranasal oxytocin administration attenuates the ACTH stress response in monkeys. Psycho- neuroendocrinology 2005; 30: 924-9. [CrossRef]
• Miller AA, De Silva TM, Jackman KA, Sobey CG. Effect of gender and sex hormones on vascular oxidative stress. Clin Exp Pharmacol Physiol 2007; 34: 1037-43. [CrossRef]
• Hernández I, Delgado JL, Díaz J, Quesada T, Teruel MJ, Llanos MC et al. 17beta-Estradiol prevents oxidative stress and decrease blood pressure in ovariectomized rats. Am J Physiol Regul Integr Comp Physiol 2000; 279: 1599-1605.
• Subbiah MT. Mechanisms of cardioprotection by estrogens. Proc Soc Ex- pert Biol Med 1998; 217: 23-9. [CrossRef]
• Sanchez-Rodriguez MA, Zacarias-Flores M, Arronte-Rosales A, Cor- rea-Muno E, Mendoza-Nunez VM. Menopause as risk factor for oxidative stress. Menopause 2012; 19: 361-7. [CrossRef]
• Sahin E, Gümüşlü S. Stress-dependent induction of protein oxidation, lipid peroxidation and anti- oxidants in peripheral tissues of rats: com- parison of three stress models (immobilization, cold and immobiliza- tion-cold). Clin Exp Pharmacol Physiol 2007; 34: 425-31. [CrossRef]