Mifepristone Ameliorates Sleep Deprivation - Induced Oxidative Stress in the Testis of Rats
Keywords:
Chronic Stress, Inflammation, Mifepristone, Oxidative Stress, Sleep deprivationAbstract
Sleep deprivation is becoming an everyday experience and has been associated with generation of chronic stress and low level of testosterone. This study aimed to evaluate the influence of mifepristone on testicular oxidative stress and serum inflammatory markers in sleep deprivation induced chronic stress in rats. Twenty five rats were divided into five groups (n=5) and designated as follows: Group 1: Control, Group 2: sleep deprived (SD), Group 3: sleep deprived and sleep recovery (SD+SR), Group 4: sleep deprived mifepristone treated (SD+MIF), Group 5: sleep deprived and recovery mifepristone treated (SD+SR+MIF). Rats were sleep deprived for five days, mifepristone 10mg/kg was given orally for mifepristone treated groups while recovery groups were allowed to recover for five days. At the end of the experiment, cortisol, testosterone, interleukin 6 (IL-6) and c reactive protein (CRP) were analysed while testicular malondialdehyde (MDA), catalase (CAT), and glutathione (GSH) were also evaluated. Rats in SD group had significantly increased level of MDA and cortisol, IL-6 and CRP levels (p<0.05), while showing significantly reduced the levels of testosterone, GSH, and CAT (p<0.05). Treatment with mifepristone reversed the changes in the MDA, GSH, CAT, cortisol, testosterone levels (p<0.05), while only sleep deprived recovery (SD+SR) reversed changes in IL-6 and CRP. The present findings indicate that mifepristone possesses antioxidant properties which may ameliorate the imbalance between reactive oxygen species (ROS) and production of antioxidant enzymes in the testis. However, sleep recovery is important in reversing inflammatory changes due to sleep deprived induced chronic stress.
References
Aebi, H., (1984):. Catalase in vitro, in: Methods in Enzymology. Elsevier, pp. 121–126.
Albertson, B.D., Hill, R.B., Sprague, K.A., Wood, K.E., Nieman, L.K., Loriaux, D.L., (1994): Effect of the antiglucocorticoid RU486 on adrenal steroidogenic enzyme activity and steroidogenesis. Eur. J. Endocrinol. 130, 195–200.
Almeida, S.A., Petenusci, S.O., Franci, J.A., Silva, A.R.E., Carvalho, T.L., (2000): Chronic immobilization-induced stress increases plasma testosterone and delays testicular maturation in pubertal rats. Andrologia 32, 7–11.
Belanoff, J.K., Jurik, J., Schatzberg, L.D., DeBattista, C., Schatzberg, A.F., (2002): Slowing the progression of cognitive decline in Alzheimer’s disease using mifepristone. J. Mol. Neurosci. 19, 201–206.
Blasey, C.M., DeBattista, C., Roe, R., Block, T., Belanoff, J.K., (2009): A multisite trial of mifepristone for the treatment of psychotic depression: a site-by-treatment interaction. Contemp. Clin. Trials 30, 284–288.
Chrousos, G.P., (1995): The hypothalamic–pituitary–adrenal axis and immune-mediated inflammation. N. Engl. J. Med. 332, 1351–1363.
Cote, K.A., McCormick, C.M., Geniole, S.N., Renn, R.P., MacAulay, S.D., (2013): Sleep deprivation lowers reactive aggression and testosterone in men. Biol. Psychol. 92, 249–256.
Dalal, J., Kumar, P., Chandolia, R.K., Pawaria, S., Rajendran, R., Sheoran, S., Andonissamy, J., Kumar, D., (2019): A new role for RU486 (mifepristone): it protects sperm from premature capacitation during cryopreservation in buffalo. Sci. Rep. 9, 6712.
Dallman, M.F., Pecoraro, N.C., la Fleur, S.E., (2005): Chronic stress and comfort foods: self-medication and abdominal obesity. Brain. Behav. Immun. 19, 275–280.
Damayanthi, D., Azman, M.A.B., Aminuddin, A.H.K., Hamid, A., Nwe, K.H.H., (2011): Effects of Smilax myosotiflora on testicular 11?-hydroxysteroid dehydro-genase oxidative activity and plasma hormone levels in rats.
Devasagayam, T.P.A., Boloor, K.K., Ramasarma, T., (2003): Methods for estimating lipid peroxidation: an analysis of merits and demerits. Indian J. Biochem. Biophys. 40, 300–308.
Dimitrov, I., Kamenov, V., Angelova, P., Petrov, M., (2014): Concentration of C-reactive protein in white adipose tissue, liver and blood serum of male Wistar rats. Trakia J. Sci. 12, 29–33.
Dong, Q., Salva, A., Sottas, C.M., Niu, E., Holmes, M., Hardy, M.P., (2004): Rapid glucocorticoid mediation of suppressed testosterone biosynthesis in male mice subjected to immobilization stress. J. Androl. 25, 973–981.
El-Aziz, E.A.A., Mostafa, D.G., (2012): Impact of sleep deprivation and sleep recovery on reproductive hormones and testicular oxidative stress in adult male rats. AAMJ 10, 1.
El-Sayed, A.-F.M., Abdel-Aziz, E.-S.H., Abdel-Ghani, H.M., (2012): Effects of phytoestrogens on sex reversal of Nile tilapia (Oreochromis niloticus) larvae fed diets treated with 17α-Methyltestosterone. Aquaculture 360, 58–63.
Frungieri, M.B., Zitta, K., Pignataro, O.P., Gonzalez-Calvar, S.I., Calandra, R.S., 2002. Interactions between testicular serotoninergic, catecholaminergic, and corticotropin-releasing hormone systems modulating cAMP and testosterone production in the golden hamster. Neuroendocrinology 76, 35–46.
Gao, H.-B., Tong, M.-H., Hu, Y.-Q., Guo, Q.-S., Ge, R., Hardy, M.P., (2002): Glucocorticoid induces apoptosis in rat leydig cells. Endocrinology 143, 130–138.
Ghosh, D., Das, S., Maiti, R., Jana, D., Das, U.B., (2002): Testicular toxicity in sodium fluoride treated rats: association with oxidative stress. Reprod. Toxicol. 16, 385–390.
Glavas, M.M., Yu, W.K., Weinberg, J., (2006): Effects of mineralocorticoid and glucocorticoid receptor blockade on hypothalamic–pituitary–adrenal function in female rats prenatally exposed to ethanol. Alcohol. Clin. Exp. Res. 30, 1916–1924.
Hannibal, K.E., Bishop, M.D., (2014):Chronic stress, cortisol dysfunction, and pain: a psychoneuroendocrine rationale for stress management in pain rehabilitation. Phys. Ther. 94, 1816–1825.
Hardeland, R., (2018): Melatonin and inflammation—Story of a double-edged blade. J. Pineal Res. 65, e12525.
Honess, P.E., Marin, C.M., (2006). Behavioural and physiological aspects of stress and aggression in nonhuman primates. Neurosci. Biobehav. Rev. 30, 390–412.
Im, A., Appleman, L.J., (2010): Mifepristone: pharmacology and clinical impact in reproductive medicine, endocrinology and oncology. Expert Opin. Pharmacother. 11, 481–488.
Johnson, M., (2006): Molecular mechanisms of β2-adrenergic receptor function, response, and regulation. J. Allergy Clin. Immunol. 117, 18–24.
Juliet, P.A., Hayashi, T., Daigo, S., Matsui-Hirai, H., Miyazaki, A., Fukatsu, A., Funami, J., Iguchi, A., Ignarro, L.J., (2004): Combined effect of testosterone and apocynin on nitric oxide and superoxide production in PMA-differentiated THP-1 cells. Biochim. Biophys. Acta BBA-Mol. Cell Res. 1693, 185–191.
Kakade, A.S., Kulkarni, Y.S., (2014): Mifepristone: current knowledge and emerging prospects. J. Indian Med. Assoc. 112, 36–40.
Khalil, R.B., Smayra, V., Saliba, Y., Hajal, J., Bakhos, J.-J., Souaiby, L., Richa, S., Tamraz, J., Farès, N., (2018): Mifepristone reduces hypothalamo-pituitary-adrenal axis activation and restores weight loss in rats subjected to dietary restriction and methylphenidate administration. Neurosci. Res. 135, 46–53.
Kinn Rød, A.M., Harkestad, N., Jellestad, F.K., Murison, R., (2017): Comparison of commercial ELISA assays for quantification of corticosterone in serum. Sci. Rep. 7.
Kolmus, K., Tavernier, J., Gerlo, S., (2015): β2-Adrenergic receptors in immunity and inflammation: stressing NF-κB. Brain. Behav. Immun. 45, 297–310.
Kumar, P., Saini, M., Kumar, D., Bharadwaj, A., Yadav, P.S., (2017): Estimation of endogenous levels of osteopontin, total antioxidant capacity and malondialdehyde in seminal plasma: application for fertility assessment in buffalo (Bubalus bubalis) bulls. Reprod. Domest. Anim. 52, 221–226.
Leenaars, C.H., Dematteis, M., Joosten, R.N., Eggels, L., Sandberg, H., Schirris, M., Feenstra, M.G., Van Someren, E.J., (2011): A new automated method for rat sleep deprivation with minimal confounding effects on corticosterone and locomotor activity. J. Neurosci. Methods 196, 107–117.
Li, A., Felix, J.C., Yang, W., Jain, J.K., (2008): Effect of mifepristone on the expression of endometrial secretory leukocyte protease inhibitor in new medroxyprogesterone acetate users. Fertil. Steril. 90, 872–875.
Mackin, P., Young, A.H., (2004: Rapid cycling bipolar disorder: historical overview and focus on emerging treatments. Bipolar Disord. 6, 523–529.
Manna, I., Jana, K., Samanta, P.K., (2004): Intensive swimming exercise-induced oxidative stress and reproductive dysfunction in male Wistar rats: protective role of α-tocopherol succinate. Can. J. Appl. Physiol. 29, 172–185.
Manna, I., Jana, K., Samanta, P.K., (2003): Effect of intensive exercise-induced testicular gametogenic and steroidogenic disorders in mature male Wistar strain rats: a correlative approach to oxidative stress. Acta Physiol. Scand. 178, 33–40.
Mantyh, P.W., Rogers, S.D., Allen, C.J., Catton, M.D., Ghilardi, J.R., Levin, L.A., Maggio, J.E., Vigna, S.R., (1995): Beta 2-adrenergic receptors are expressed by glia in vivo in the normal and injured central nervous system in the rat, rabbit, and human. J. Neurosci. 15, 152–164.
McEwen, B.S., (2007): Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol. Rev. 87, 873–904.
Miech, R.P., (2005):. Pathophysiology of mifepristone-induced septic shock due to Clostridium sordellii. Ann. Pharmacother. 39, 1483–1488.
Miller, A.H., Maletic, V., Raison, C.L., (2009): Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741.
Miller, G.E., Cohen, S., Ritchey, A.K., (2002) Chronic psychological stress and the regulation of pro-inflammatory cytokines: a glucocorticoid-resistance model. Health Psychol. 21, 531.
Mingoti, G.Z., Pereira, R.N., Monteiro, C.M.R., (2003): Fertility of male adult rats submitted to forced swimming stress. Braz. J. Med. Biol. Res. 36, 677–682.
Mohamad, N.-V., Wong, S.K., Wan Hasan, W.N., Jolly, J.J., Nur-Farhana, M.F., Ima-Nirwana, S., Chin, K.-Y., (2019): The relationship between circulating testosterone and inflammatory cytokines in men. Aging Male 22, 129–140.
Monder, C., Sakai, R.R., Miroff, Y., Blanchard, D.C., Blanchard, R.J., (1994): Reciprocal changes in plasma corticosterone and testosterone in stressed male rats maintained in a visible burrow system: evidence for a mediating role of testicular 11 beta-hydroxysteroid dehydrogenase. Endocrinology 134, 1193–1198.
Nirupama, M., Yajurvedi, H., (2015): Efficacy of Ashwagandha (Withania somnifera L.) root extracts in preventing stress induced testicular damage in rat. Eur. J. Biomed. Pharm. Sci. 2, 413–424.
Oh, M.M., Kim, J.W., Jin, M.H., Kim, J.J., Moon, D.G., (2012): Influence of paradoxical sleep deprivation and sleep recovery on testosterone level in rats of different ages. Asian J. Androl. 14, 330–334.
Olayaki, L.A., Sulaiman, S.O., Anoba, N.B., (2015): Vitamin C prevents sleep deprivation-induced elevation in cortisol and lipid peroxidation in the rat plasma. Niger. J. Physiol. Sci. 30, 5–9.
Padro, C.J., Sanders, V.M., (2014): Neuroendocrine regulation of inflammation, in: Seminars in Immunology. Elsevier, pp. 357–368.
Rajaratnam, S.M., Arendt, J., (2001): Health in a 24-h society. The Lancet 358, 999–1005.
Research, I. for L.A., (1996): National Research Council: Guide for the Care and Use of Laboratory Animals. National Academy Press Washington DC.
Román, V., Hagewoud, R., Luiten, P.G., Meerlo, P., (2006): Differential effects of chronic partial sleep deprivation and stress on serotonin-1A and muscarinic acetylcholine receptor sensitivity. J. Sleep Res. 15, 386–394.
Silva, R.H., Abilio, V.C., Takatsu, A.L., Kameda, S.R., Grassl, C., Chehin, A.B., Medrano, W.A., Calzavara, M.B., Registro, S., Andersen, M.L., (2004): Role of hippocampal oxidative stress in memory deficits induced by sleep deprivation in mice. Neuropharmacology 46, 895–903.
Swami, C.G., Jeganathan Ramanathan, C., (2007): Noise exposure effect on testicular histology, morphology and on male steroidogenic hormone. Malays. J. Med. Sci. MJMS 14, 28.
Theron, A.J., Steel, H.C., Tintinger, G.R., Feldman, C., Anderson, R., (2013): Can the anti-inflammatory activities of β2-agonists be harnessed in the clinical setting? Drug Des. Devel. Ther. 7, 1387.
Tufik, S., Andersen, M.L., Bittencourt, L.R., Mello, M.T. de, (2009): Paradoxical sleep deprivation: neurochemical, hormonal and behavioral alterations. Evidence from 30 years of research. An. Acad. Bras. Ciênc. 81, 521–538.
Villafuerte, G., Miguel-Puga, A., Murillo Rodríguez, E., Machado, S., Manjarrez, E., Arias-Carrión, O., (2015): Sleep deprivation and oxidative stress in animal models: a systematic review. Oxid. Med. Cell. Longev. 2015.
Whirledge, S., Cidlowski, J.A., (2010): Glucocorticoids, stress, and fertility. Minerva Endocrinol. 35, 109.
Wittert, G., (2014): The relationship between sleep disorders and testosterone in men. Asian J. Androl. 16, 262.
Wolkow, A., Aisbett, B., Reynolds, J., Ferguson, S.A., Main, L.C., (2015): Relationships between inflammatory cytokine and cortisol responses in firefighters exposed to simulated wildfire suppression work and sleep restriction. Physiol. Rep. 3, e12604.
Yang, C.-Y., Lin, M.-T., (2002): Oxidative stress in rats with heatstroke-induced cerebral ischemia. Stroke 33, 790–794.
Yaribeygi, H., Panahi, Y., Sahraei, H., Johnston, T.P., Sahebkar, A., (2017): The impact of stress on body function: A review. EXCLI J. 16, 1057.
Yazawa, H., Sasagawa, I., Nakada, T., (2000): Apoptosis of testicular germ cells induced by exogenous glucocorticoid in rats. Hum. Reprod. 15, 1917–1920.
Yoga, R., Theis, J.C., Walton, M., Sutherland, W., (2009): Interleukin-6 as an early marker for fat embolism. J. Orthop. Surg. 4, 18.
Zelena, D., Makara, B.G., (2015): Steroids: The physiologic and pharmacologic effects of glucocorticoids. Orv. Hetil. 156, 1415–1425
