Zataria multiflora extract reverses lipopolysaccharide-induced anxiety and depression behaviors in rats

Document Type : Original Research Article


1 Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

2 Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.

3 Critical Care Nursing, Faculty of Nursing and Midwifery, Jiroft University of Medical Science, Jiroft, Iran

4 Department of Physiology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran


Objective: Stressors have an important role in sickness behaviors. We checked the effect of Zataria multiflora (ZM) extract against lipopolysaccharide (LPS)-induced anxiety and depression behaviors in rats.
Material and Methods: Rats were distributed in the following groups (n=10): Control, LPS (1 mg/kg), LPS-ZM50, LPS-ZM100 and LPS-ZM200. LPS was syringed intraperitoneally (ip) 2 hr before performing behavioral tests. LPS-ZM groups were treated with 50, 100 and 200 mg/kg (ip) of ZM extract 30 min before LPS administration. Open field (OF), elevated plus maze (EPM) and forced swimming (FS) tests were done. White blood cell (WBC) was counted in all groups.
Results: In OF, pretreatment with ZM extract augmented the number of lines crossed and traveled distance in central and peripheral areas. The rats treated with ZM extract spent more time in the central zone and less time in the peripheral area compared to the LPS group. In EPM, the number of entries into the open and closed arms and stop time in the open arms in LPS-ZM groups were higher than the LPS group. The stop time in the closed arms of ZM-LPS groups was less than the LPS group. In FS test, swimming and climbing time in groups treated with ZM extract was more than the LPS group while their immobility time was less. WBC count in the LPS-ZM100 and LPS-ZM200 was lower than that of the LPS group.  
Conclusion: Based on the results, pretreatment with ZM extract restituted anxiety and depression caused by LPS in rats. This effect of ZM was associated with amelioration of LPS-promoted inflammation.


Main Subjects

Almahozi A, Radhi M, Alzayer S, Kamal A. 2019. Effects of memantine in a mouse model of postoperative cognitive dysfunction. Behav Sci, pii: E24.
Anisman H, Merali, Z. 2002. Cytokines, stress, and depressive illness. Brain Behav Immun, 16: 513-24.
Ano Y, Ohya R, Kita M, Taniguchi Y, Kondo K. 2019. Theaflavins improve memory impairment and depression-like behavior by regulating microglial activation. Molecules, pii: E467.
Arab HA, Fathi M, Mortezai E, Hosseinimehr SJ. 2015. Chemoprotective effect of thymol against genotoxicity induced by bleomycin in human lymphocytes. Pharm Biomed Res, 1: 26-31.
kul’chyns’kyi AB, Kyjenko VM, Zukow W, Popovych IL. 2017. Causal neuro-immune relationships at patients with chronic pyelonephritis and cholecystitis. Correlations between parameters EEG, HRV and white blood cell count. Open Med, 12: 201-213.
Bannerman DD, Paape MJ, Hare WR, Sohn EJ, 2003. Increased levels of LPS-binding protein in bovine blood and milk following bacterial lipopolysaccharide challenge. J Dairy Sci, 86:3128-3137.
Bedaso A, Ayalew M. 2019. Preoperative anxiety among adult patients undergoing elective surgery: a prospective survey at a general hospital in Ethiopia. Patient Saf Surg, 13: 18.
Bennett S, Thomas AJ. 2014. Depression and dementia: cause, consequence or coincidence? Maturitas, 79: 184-190.
Biesmans S, Meert TF, Bouwknecht JA, Acton PD, Davoodi N, De Haes P, Kuijlaars J, Langlois X, Matthews LJ, Verdonck L. 2013. Systemic immune activation leads to neuroinflammation and sickness behavior in mice. Mediators Inflamm, 2013: 1-14.
Boskabady MH, Gholami Mhtaj L. 2014. Effect of the Zataria multiflora on systemic inflammation of experimental animals model of COPD. Biomed Res Int, 2014: 802189.
Boskabady MH, Gholami Mahtaj L. 2015. Lung inflammation changes and oxidative stress induced by cigarette smoke exposure in guinea pigs affected by Zataria multiflora and its constituent, carvacrol. BMC Complement Altern Med, 15: 1-10.
Brymer KJ, Romay Tallon R, Allen J, Caruncho HJ, Kalynchuk LE. 2019. Exploring the potential antidepressant mechanisms of TNFα antagonists. Front Neurosci, 13: 98.
Cordeiro RC, Chaves Filho AJ, Soaresgomes N, Tomaz VS, Medeiros CD, Queiroz AI, Maes M, Macedo DS, Carvalho AF. 2019. Leptin prevents lipopolysaccharide-induced depressive-like behaviors in mice: involvement of dopamine receptors. Front Psychiatry, 10: 125.
Cryan JF, Markou A, Lucki I. 2002. Assessing antidepressant activity in rodents: recent developments and future needs. Trends in pharmacological sciences, 23: 238-245.
Dantzer R, O'connor JC, Freund GG, Johnson RW, Kelley KW. 2008. From inflammation to sickness and depression: when the immune system subjugates the brain. Trends Pharmacol Sci, 23: 238-45.
Dinel AL, André C, Aubert A, Ferreira G, Layé S, Castanon N. 2014. Lipopolysaccharide-induced brain activation of the indoleamine 2, 3-dioxygenase and depressive-like behavior are impaired in a mouse model of metabolic syndrome. Psychoneuroendocrinology, 40: 48-59.
Fazeli MR, Amin G, Attari MMA, Ashtiani H, Jamalifar H, Samadi N. 2007. Antimicrobial activities of Iranian sumac and avishan-e shirazi (Zataria multiflora) against some food-borne bacteria. Food Control, 18: 646-649.
Gu Z, Chu L, Han Y. 2019. Therapeutic effect of resveratrol on mice with depression. Exp Ther Med, 17: 3061-3064.
Hankin BL. 2006. Adolescent depression: description, causes, and interventions. Epilepsy Behav,8: 102-114.
Hart BL. 1988. Biological basis of the behavior of sick animals. Neurosci Biobehav Rev, 12: 123-137.
Hosseinimehr SJ, Ahmadashrafi S, Naghshvar F, Ahmadi A, Ehasnalavi S, Tanha M. 2010. Chemoprotective effects of Zataria multiflora against genotoxicity induced by cyclophosphamide in mice bone marrow cells. Integr Cancer Ther, 9: 219-223.
Hosseinimehr SJ, Mahmoudzadeh A, Ahmadi A, Ashrafi SA, Shafaghati N, Hedayati N. 2011. The radioprotective effect of Zataria multiflora against genotoxicity induced by γ irradiation in human blood lymphocytes. Cancer Biother Radiopharm, 26: 325-329.
Hosseinzadeh H, Ramezani M, Salmani GA. 2000. Antinociceptive, anti-inflammatory and acute toxicity effects of Zataria multiflora Boiss extracts in mice and rats. J Ethnopharmacol, 73: 379-385.
Karimi S, Hosseinimehr SJ, Mohammadi HR, Khalatbary AR, Amiri FT. 2018. Zataria multiflora ameliorates cisplatin-induced testicular damage via suppression of oxidative stress and apoptosis in a mice model. Iran J Basic Med Sci, 21: 607-614.
Khazdair MR, Anaeigoudari A, Hashemzehi M, Mohebbati R. 2019. Neuroprotective potency of some spice herbs, a literature review. J Tradit Complement Med, 9: 98-105.
Kianmehr M, Haghmorad D, Nosratabadi R, Rezaei A, Alavinezhad A, Boskabady MH. 2017. The effect of Zataria multiflora on Th1/Th2 and Th17/T regulatory in a mouse model of allergic asthma. Front Pharmacol, 8: 458.
Li H, Lin S, Qin T, Li H, Ma Z, Ma S. 2017. Senegenin exerts anti-depression effect in mice induced by chronic un-predictable mild stress via inhibition of NF-κB regulating NLRP3 signal pathway. Int Immunopharmacol, 53: 24-32.
Maes M, Kubera M, Leunis JC, Berk M. 2012. Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut. J Affect Disord, 141: 55-62.
Mahmoodi M, Koohpeyma F, Saki F, Maleksabet A. 2019. The protective effect of Zataria multiflora Boiss. hydroalcoholic extract on TNF-α production, oxidative stress, and insulin level in streptozotocin-induced diabetic rats. Avicenna J Phytomed, 9: 72-83.
Mello BS1, Monte AS, McIntyre RS, Soczynska JK, Custódio CS, Cordeiro RC, Chaves JH, Vasconcelos SM, Nobre HV JR, Florenço de Sousa FC, Hyphantis TN, Carvalho AF, Macêdo DS. 2013. Effects of doxycycline on depressive-like behavior in mice after lipopolysaccharide (LPS) administration. J Psychiatr Res, 47: 1521-9.
Miller AH, Maletic V, Raison CL. 2009. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry, 65: 732-741.
Mohebbati R, Paseban M, Beheshti F, Soukhtanloo M, Shafei MN, Rakhshandeh H, Rad AK. 2018. The preventive effects of standardized extract of Zataria multiflora and carvacrol on acetaminophen-induced hepatotoxicity in rat: Zataria multiflora and carvacrol and hepatotoxicity. J Pharmacopuncture, 21: 249-257.
Nakhai LA, Mohammadirad A, Yasa N, Minaie B, Nikfar S, Ghazanfari G, Zamani MJ, Dehghan G, Jamshidi H, Boushehri VS. 2007. Benefits of Zataria multiflora Boiss in experimental model of mouse inflammatory bowel disease. Evid Based Complement Alternat Med, 4: 43-50.
Normandeau CP, Ventura Silva AP, Hawken ER, Angelis S, Sjaarda C, Liu X, Pêgo JM, Dumont ÉC. 2018. A key role for neurotensin in chronic-stress-induced anxiety-like behavior in rats. Neuropsychopharmacology, 43: 285-293.
Norooznezhad AH, Keshavarz M, Norooznezhad F, Mansouri K. 2017. Inhibition of angiogenesis: A novel effect of Zataria multiflora. Int J Hematol Oncol Stem Cell Res, 11: 96-101.
O’brien D, Harvey K, Howse J, Reardon T, Creswell C. 2016. Barriers to managing child and adolescent mental health problems: a systematic review of primary care practitioners’ perceptions. Br J Gen Pract, 66: 693-707.
O’connor JC, Satpathy A, Hartman ME, Horvath EM, Kelley KW, Dantzer R, Johnson RW, Freund GG. 2005. IL-1β-mediated innate immunity is amplified in the db/db mouse model of type 2 diabetes. J Immunol, 174: 4991-7.
Sharififar F, Moshafi M, Mansouri S, Khodashenas M, Khoshnoodi M. 2007. In vitro evaluation of antibacterial and antioxidant activities of the essential oil and methanol extract of endemic Zataria multiflora Boiss. Food control, 18:800-805.
Slavich GM, Irwin MR. 2014. From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull, 140: 774-815.
Wang LR, Kim SH, Baek SS. 2019. Effects of treadmill exercise on the anxiety-like behavior through modulation of GSK3β/β-catenin signaling in the maternal separation rat pup. J Exerc Rehabil, 15: 206-212.
Wang Y, Huang M, Lu X, Wei R, Xu J. 2017. Ziziphi spinosae lily powder suspension in the treatment of depression-like behaviors in rats. BMC Complement Altern Med, 17: 238.
Yeung KS, Hernandez M, Mao JJ, Haviland I, Gubili J. 2018. Herbal medicine for depression and anxiety: A systematic review with assessment of potential psycho‐oncologic relevance. Phytother Res, 32: 865-891.
Zhang X, Jia N, Zhao X, Tang G, Guan L, Wang D, Sun H, Li H, Zhu Z. 2013. Involvement of pGluR1, EAAT2 and EAAT3 in offspring depression induced by prenatal stress. Neuroscience, 250: 333-41.
Zheng X, Cheng Y, Chen Y, Yue Y, Li Y, Xia S, Li Y, Deng H, Zhang J, Cao Y. 2019. Ferulic acid improves depressive-like behavior in prenatally-stressed offspring rats via anti-inflammatory activity and HPA axis. Int J Mol Sci, pii: E493.