Oxidative stress plays a pivotal role in the pathophysiology and pathogenesis of mental diseases, such as depression or anxiety. Psychological stress induced by predatory stimulus is one of the models that explain how induced affective behavior is manifested as a depression-like state. Quercetin is a flavonoid that exhibits potential pharmacological activity on mental diseases. Thus, the present study was designed to investigate the effect of quercetin on innate fear and affective behavior induced by repeated predator stress exposure on mice.
Materials and methods
ICR mice were exposed to predatory stress for 3 days. Quercetin at a dose of 50 mg/kg was given intraperitoneally along with stress induction. The freezing behavior during the stress induction was analyzed. The anxiety-like and depressive-like behaviors and cognitive and motor functions were examined on the last day of induction.
Predatory stress increased the affective behaviors (anxiety-like and depressive-like behaviors) and produced freezing behavior without alterations in the cognitive function and exploratory behavior. Treatment with quercetin 50 mg/kg attenuated the freezing, anxiety-like and depressive-like behaviors.
Repeated predator stress exposure causes both innate fear and depression-like state for the prey animals. Quercetin may have a protective effect against depression and alleviates the fear of traumatic events.
Research funding: This work was supported by research grants from the Tahir Professorship Program and PDUPT 2019 provided by the Indonesian Ministry of Research Technology and Higher Education.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: The authors state no conflict of interest.
Ethical approval: All experiments were performed at the Laboratory of Animal Research, Faculty of Pharmacy, Universitas Airlangga in accordance with the guide for care and use of laboratory animals issued by National Institutes of Health revised in 1985. The protocol was approved by the ethical committee, Faculty of Veterinary, Universitas Airlangga with no. 2.KE.007.05.2019.
 Smith K. Mental health: a world of depression. Nature 2014;515:181.10.1038/515180aSearch in Google Scholar PubMed
 Kessler RC. The effects of stressful live events on depression. Ann Rev Psychol 1997;48:191–214.10.1146/annurev.psych.48.1.191Search in Google Scholar PubMed
 Post RM. Transduction of psychosocial stress into the neurobiology of recurrent affective behavior disorder. Am J Psychiatry 1992;149:999–1010.10.1176/ajp.149.8.999Search in Google Scholar PubMed
 Hirschfeld RM, Weissman MM. Risk factor for major depression and bipolar disorder. In: Davis KL, Charney D, Coyle JT and Nemeroff C, editors, Neuropsychophamacology: The fifth generation of progress. Brentwood, TN: American College of Neuropsychopharmacology, 2002; Chapter 70, pp. 1017–25 .Search in Google Scholar
 Khotib J, Rahmadi M, Ardianto C, Nisak K, Oktavia R, Ratnasari A, et al. Selective serotonin reuptake inhibitor fluvoxamine ameliorates stress- and NSAID-induced peptic ulcer possibly by involving Hsp70. J Basic Clin Physiol Pharmacol 2019;30:195–203.10.1515/jbcpp-2018-0067Search in Google Scholar PubMed
 Yehuda R. Post-traumatic stress disorder. N Engl J Med 2002;346:108–114.10.1002/0470018860.s00415Search in Google Scholar
 Cobley JN, Fiorello ML, Bailey DM. 13 reasons why the brain is susceptible to oxidative stress. Redox Biol 2018;15:290–503.10.1016/j.redox.2018.01.008Search in Google Scholar PubMed PubMed Central
 Burgado J, Harrell SS, Eacret D, Reddy R, Barnum CJ, Tansey G, et al. Two weeks of predatory stress induces anxiety-like behavior with co-morbid depressive-like behavior in adult male mice. Behav Brain Res 2014;275:120–5.10.1016/j.bbr.2014.08.060Search in Google Scholar PubMed PubMed Central
 Liu YX, Cheng YN, Miao YL, Wei DL, Zhao LH, Luo MJ, et al. Psychological stress on female mice diminishes the developmental potential of oocytes: a study using the predatory stress model. PLoS One 2012;7:1–8.10.1371/journal.pone.0048083Search in Google Scholar PubMed PubMed Central
 Panche AN, Diwan AD, Chandra SR. Flavonoids: an overview. J Nutr Sci 2016;5:1–15.10.1017/jns.2016.41Search in Google Scholar PubMed PubMed Central
 Dajas F, Abin-Carriquiry JA, Arredondo F, Blasina F, Echeverry C, Martinez M, et al. Quercetin in brain diseases: potential and limits. Neurochem Int 2015;89:140–8.10.1016/j.neuint.2015.07.002Search in Google Scholar PubMed
 Jarial R, Shard A, Thakur S, Sakinah M, Zularisam AW, Rezania S, et al. Characterization of flavonoids from fern Cheilanthes tenuifolia and evaluation of antioxidant, antimicrobial and anticancer activities. J King Saud Univ 2017;30:425–32.10.1016/j.jksus.2017.04.007Search in Google Scholar
 Jakhar R, Paul S, Park YR, Han J, Kang SC. 3,5,7,3’,4’-Pentamethoxyflavone, a quercetin derivative protects DNA from oxidative challenges: potential mechanism of action. J Photochem Photobiol B 2014;131:96–103.10.1016/j.jphotobiol.2014.01.003Search in Google Scholar PubMed
 Indriyanti N, Soeroso J, Khotib J. FOXP3 modulation of quercetin-3-o-rhamnoside and its impacts on lupus nephritis mice. J Young Pharm 2018;10:183–6.10.5530/jyp.2018.10.41Search in Google Scholar
 Rinwa P, Kumar A. Quercetin suppress microglial neuro-inflammatory response and induce antidepressant-like effect in olfactory bulbectomized rats. Neuroscience 2013;255:86–98.10.1016/j.neuroscience.2013.09.044Search in Google Scholar PubMed
 Holzmann I, da Silva LM, da Silva JA, Steimbach VM, de Souza MM. Antidepressant-like effect of quercetin in bulbectomized mice and involvement of the antioxidant defenses, and the glutamatergic and oxidonitrergic pathways. Pharmacol Biochem Behav 2015;135:55–63.10.1016/j.pbb.2015.07.003Search in Google Scholar PubMed
 Mehta V, Parashar A, Udayabanu M. Quercetin prevents chronic unpredictable induced behavioural dysfunction in mice by alleviating hippocampal oxidative and inflammatory stress. Physiol Behav 2017;171:69–78.10.1016/j.physbeh.2017.01.006Search in Google Scholar PubMed
 Fanselow MS. Factor governing one-trial contextual conditioning. Anim Learn Behav 1990;18:264–70.10.3758/BF03205285Search in Google Scholar
 Paylor R, Tracy R, Wehner J, Rudy JW. C57BL/6 and DBA/2 mice differ on contextual but not auditory fear conditioning. Behav Neurosci 1994;108:810–7.10.1037/0735-7044.108.4.810Search in Google Scholar
 Steru L, Chermat R, Thierry B, Simon P. The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 1985;85:367–70.10.1007/BF00428203Search in Google Scholar PubMed
 Mentari IA, Naufalina R, Rahmadi M, Khotib J. Development of ischemic stroke model by right unilateral common carotid artery occlusion (RUCCAO) method. Fol Med Indonesiana 2018;54:200–6.10.20473/fmi.v54i3.10015Search in Google Scholar
 Khotib J, Mentari IA, Rahmadi M. Erythropoietin potential as an antiapoptotic agent in iscemic stroke using unilateral right common carotid artery occlusion (RUCCAO) model. Indian J Public Health Res Dev 2019;10:1184–9.10.5958/0976-5506.2019.00871.4Search in Google Scholar
 Jaggi AS, Bhatia N, Kumar N, Singh N, Anand P, Dhawan R. A review on animal models for screening potential anti-stress agents. Neurol Sci 2011;32:993–1005.10.1007/s10072-011-0770-6Search in Google Scholar PubMed
 Toumi ML, Merzoug S, Tahraoui A. Effects of quercetin on predator stress-related hematological and behavioral alternations in pregnant rats and their offspring. J Biosci 2016;41:237–49.10.1007/s12038-016-9613-1Search in Google Scholar PubMed
 Wang Y, Cao L, Chia Y, Matsuo T, Wu K, Asher G, et al. Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviours. Nat Commun 2018;9:1–15.Search in Google Scholar
 Hassan W, de Castro Gomes V, Pinton S, da Rocha JB, Landeira-Fernandex J. Association between oxidative stress and contextual fear conditioning in Carioca high- and low-conditioned freezing rats. Brain Res 2013;1512:60–7.10.1016/j.brainres.2013.03.039Search in Google Scholar PubMed
 Gard R, Kumar A. Possible role of citalopram and desipramine against sleep deprivation-induced anxiety like-behavior alterations and oxidative damage in mice. Indian J Exp Biol 2008;46:770–6.Search in Google Scholar
© 2019 Walter de Gruyter GmbH, Berlin/Boston