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A review on humane endpoints in animal experimentation for biomedical research 2 2 Introduction: The use of animals in experiments and their role in the development of medical sciences are undeniable. Humane endpoints terminate pain and distress in laboratory animals, which are experimented in painful procedures and an involuntary manner. This study was going to review studies published in this area to assist researchers in developing their approach. Methods: Articles used in this review study were obtained from relevant databases including Pubmed, Scopus, Science Direct, OVID, SID, Magiran and Google scholar. Results: “Humane endpoints” or killing the animal humanely means the point at which an experimental animal’s pain and/or distress is terminated. This pain and distress are not necessarily accompanied by clinical symptoms and it can also be recognized by biochemical, physiological and molecular biomarkers testing. Conclusion: Regarding the extensive use of laboratory animals, the aim is not only to take care of animals but also to develop knowledge and prevent unintentional animal suffering and death. Increasing awareness of ethical issues regarding research animal use needs scientific information and designing experiments, which are terminated immediately after achieving main goals. Otherwise, it threatens the life of animal and leads to the animal suffering. 1 6 2020/04/24 1399/2/5 2020/07/25 1399/5/4 هوشنگ نجفی Houshang Najafi Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran iran hnajafi@kums.ac.ir رضا زارعی Reza Zarei Student Research Committee, Arak University of Medical Sciences, Arak, Iran Iran dr.ashtiyani@arakmu.ac.ir Abbas Alimoradian Abbas Alimoradian Department of Pharmacology, School of Medicine, Arak University of Medical Sciences, Arak, Iran Iran dr.alimoradian@arakmu.ac.ir Mohaddeseh Asafari Mohaddeseh Asafari Deputy of Food and Drug, Arak University of Medical Sciences, Arak, Iran Iran m.asafari@arakmu.ac.ir Mahsa Mohammadi Mahsa Mohammadi Student Research Committee, Arak University of Medical Sciences, Arak, Iran Iran dr.ashtiyani@arakmu.ac.ir Fatemeh Samadi Fatemeh Samadi Student Research Committee, Arak University of Medical Sciences, Arak, Iran Iran dr.ashtiyani@arakmu.ac.ir Majid Ramezani Majid Ramezani Department of internal Medicine, School of Medicine, Baghitallah University of Medical Sciences, Teharn, Iran Iran m_ramezani@sina.tums.ac.ir Saeed Changizi Ashtiyani Saeed Changizi Ashtiyani Department of Physiology, School of Medicine, Arak University of Medical Sciences, Arak, Iran Iran dr.ashtiyani@arakmu.ac.ir Laboratory animals Humane endpoints Animal welfare Biomedical research. Ahmadi-Noorbakhsh S. Sample size calculation for animal studies-with emphasis on the ethical principles of reduc‌tion of animal use. Res Med 2018; 42: 144-153.##Araujo FR, Paixão RL. Humane endpoint in mice by Brazilian researchers in the vaccine sector. Arq Bras Med Vet Zootec 2019; 71: 500-8. https://doi.org/10.1590/1678-4162-10524##Bhasin J, Latt R, Macallum E, McCutcheon K, Olfert E, Rain‌nie D, et al. Canadian Council on Animal Care Guidelines: choosing an appropriate endpoint in experiments. Ottawa, Ontario, Canada 1998.##Berkeley UC. Guidelines for humane endpoints in animal studies. University of California 2018.##Changizi-Ashtiyani S, Shamsi M, Cyrus A, Tabatabayei SM. Rhazes, a genius physician in the diagnosis and treatment of nocturnal enuresis in medical history. Iran Red Crescent Med J 2013; 15: 633. https://doi.org/10.5812/ircmj.5017##Changizi-Ashtiyani S, Cyrus A. Rhazes, a genius physician in diagnosis and treatment of kidney calculi in medical histo‌ry. Iran J Kidney Dis 2010; 4: 106-10.##Changizi-Ashtiyani S, Alizadeh M, Najafi H, Babaei S, Kha‌zaei M, Jafari M, Hossaini N, Avan A, Bastani B. Physalis alkekengi and Alhagi maurorum ameliorate the side effect of cisplatin-induced nephrotoxicity. Cancer Gene Ther. 2016; 23(7):235-40.##Changizi-Ashtiyani S, Zohrabi M, Hassanpoor A, Hosseini N, Hajihashemi S. Oral administration of the aqueous extract of Rosmarinus officinalis in rats before renal reperfusion injury. Iran J Kidney Dis. 2013;7(5):367-75.##Cornett EM, Jones MR, Kaye AD. Ethics of animal exper‌imentation. In Pain Springer 2019, pp. 101-4.https://doi.org/10.1007/978-3-319-99124-5_25##Council National Research. Definition of pain and distress and reporting requirements for laboratory animals: pro‌ceedings of the workshop held June 22, 2000. National Academies Press, 2000.##Council National Research. Guide for the care and use of lab‌oratory animals. National Academies Press, 2010.##Directive OJ. 63/EU of the European Parliment and of the Council on the protection of animals used for scientific purposes. Official Journal of the European Union 2010; 276: 56.##Dunlap J. Humane endpoints for animals used in training. Lab Anim 2015; 44: 71. https://doi.org/10.1038/laban.685##Faustino-Rocha AI, Ginja M, Ferreira R, Oliveira PA. Study‌ing humane endpoints in a rat model of mammary carcino‌genesis. Iran J Basic Med Sci 2019; 22: 643.##Fox JG. Laboratory animal medicine. Elsevier, 2015 . https://doi.org/10.1016/B978-0-12-409527-4.00001-8##Gauvin DV, Craig L, Boley SE. Statutory imposed terms of stress, distress, well-being and animal welfare: suggest‌ed guidelines for humane endpoints in animal studies. J Pharm Pharm Scien 2018; 2: 1-3. https://doi.org/10.24218/vjpps.2018.21##Guidelines Committee U of PIAC and U. IACUC. Rodent tu‌mor and cancer models. University of Pennsylvania 2016.##Hajar R. Animal testing and medicine. Heart views 2011; 12: 42. https://doi.org/10.4103/1995-705X.81548##Howard B, Nevalainen T, Perretta G. The COST manual of laboratory animal care and use: refinement, reduction, and research. CRC Press 2016. https://doi.org/10.1201/b13591##Mobasher M, Nakhaee N, Aramesh K, Haghdoost AK, Larija‌ni B. Phenomenologic study of experiences of researchers in Kerman and Tehran medical university about ethics in animal research. J Babol Univ Medical Sci 2009; 11: 41-8.##Morton DB. Humane endpoints in animal experimentation for biomedical research: ethical, legal and practical aspects. Humane endpoints in animal experiments for biomedical research 1999; 5-12.##Rezende AH, Peluzio MD, Sabarense CM. Animal exper‌imentation: ethics and the Brazilian legislation. Rev de Nutr 2008; 21: 237-42. https://doi.org/10.1590/S1415-52732008000200010##Russell WM, Burch RL. The principles of humane experi‌mental technique. Methuen, 1959.##Sharon-Schneidleder T, Christine A, Lorenzo DS, Federica L, Brent M, Maartje N, et al. Shortcomings of the revised «Helsinki Declaration» on ethical use of health databases. The Hastings Center, 2016.##Singh VP, Yadav S, Joshi H, Devan SR, Yadav DK, Singh RP. Recent advances in 3Rs and laboratory animal science: report on the International Conference of LASA (India). ALTEX-Alternatives to animal experimentation 2019; 36: 322-8. https://doi.org/10.14573/altex.1901041##Stokes WS. Animals and the 3Rs in toxicology research and testing: The way forward. Hum Exp Toxicol 2015; 34: 1297-303. https://doi.org/10.1177/0960327115598410##Van Zutphen LF, Baumans V, Beynen AC. Principles of labo‌ratory animal use. Elsevier, 2001.##Wright AJ, Phillpotts RJ. Humane endpoints are an objective measure of morbidity in Venezuelan encephalomyelitis virus infection of mice. Arch Virol 1998; 143: 1155-62. https://doi.org/10.1007/s007050050363## ##

Gastrointestinal and kidney manifestations in SARS-CoV and SARS-CoV-2 infections: role of angiotensin-converting enzyme 2 2 2 The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 2020, which has a substantial structural similarity to severe acute respiratory syndrome coronavirus (SARS-CoV) that caused the outbreak in 2003, is currently a threat to global health. Lung involvement is the principal clinical feature in infected patients but extra-pulmonary clinical presentations are also common. The reasons for the extensive involvement of other organs are not yet clear. Angiotensin-converting enzyme 2 (ACE2), the key peptide of renin–angiotensin system (RAS), has recently identified as a major receptor for the both SARS-CoV and SARS-CoV-2 that might be a main target of coronavirus infection. ACE2 is mainly expressed in the pulmonary pneumocytes, the small intestine enterocytes as well as the proximal tubule epithelial cells of the kidneys. In addition to the respiratory tract infection symptoms, the noticeable prevalence of gastrointestinal symptoms as well as kidney impairment in hospitalized infected patients highlights other routes of infection/transmission. In present review, we discussed the role of RAS with emphasis on ACE2 in the pathogenesis of SARS-CoV and SARS-CoV-2, particularly in gastrointestinal and kidney manifestations of the diseases. 7 20 2020/04/242020/06/15 1399/3/26 2020/07/252020/12/1 1399/9/11 Fatemeh Maghool Fatemeh Maghool Poursina Hakim Digestive Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran Iran f.maghool@pddrc.com Mohammad Hassan Emami Mohammad Hassan Emami Poursina Hakim Digestive Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran Iran mh_emami@med.mui.ac.ir Samaneh Mohammadzadeh Samaneh Mohammadzadeh Poursina Hakim Digestive Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran Iran samanemohamadzade@pddrc.com. Aida Heidari Aida Heidari Department of Cell and Molecular Biology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran Iran a.heidari@pddrc.com Tahereh Safari Tahereh Safari Infectious Diseases and Tropical Medicine Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran Iran tahereh.safari@zaums.ac.ir Severe acute respiratory syndrome Coronavirus SARS Virus Gastrointestinal Kidney ACE2 Abdulmajeed WI, Sulieman HB, Zubayr MO, Imam A, Amin A, Biliaminu SA, et al. Honey prevents neurobehavioural deficit and oxidative stress induced by lead acetate exposure in male wistar rats-a preliminary study. Metab Brain Dis 2016; 31: 37-44. https://doi.org/10.1007/s11011-015-9733-6##Adli DS. Morphometric study of hippocampal CA1 pyramidal neurons after tualang honey administration. Malaysian Journal of Microscopy 2018; 14. ##Aĭrapetiants MG, Levshina IP, Guliaeva NV. Therapeutic action of an antioxidant in chronic emotional-pain stress in the rat. Zh Vyssh Nerv Deiat Im I P Pavlova 1986; 36: 554-60. ##Akanmu MA, Olowookere TA, Atunwa SA, Ibrahim BO, Lamidi OF, Adams PA, et al. Neuropharmacological effects of Nigerian honey in mice. Afr J Tradit Complement Altern Med 2011; 8. https://doi.org/10.4314/ajtcam.v8i3.65285 ##Akouchekian S, Omranifard V, Maracy MR, Pedram A, Zefreh AA. Akouchekian S, Omranifard V, Maracy MR, Pedram A, Zefreh AA. Efficacy of herbal combination of sedge, saffron, and Astragalus honey on major neurocognitive disorder. J Res Med Sci 2018; 23. https://doi.org/10.4103/jrms.JRMS_949_17 ##Al-Rahbi B, Zakaria R, Othman Z, Hassan A, Ahmad AH. Enhancement of BDNF concentration and restoration of the hypothalamic-pituitary-adrenal axis accompany reduced depressive-like behaviour in stressed ovariectomised rats treated with either Tualang honey or estrogen. Sci World J 2014a; 2014. https://doi.org/10.1155/2014/310821 ##Al-Rahbi B, Zakaria R, Othman Z, Hassan A, Ahmad AH. Protective effects of Tualang honey against oxidative stress and anxiety-like behaviour in stressed ovariectomized rats. Int Sch Res Notices 2014b; 2014. https://doi.org/10.1155/2014/521065 ##Al-Rahbi B, Zakaria R, Othman Z, Hassan A, Ismail ZI, Muthuraju S. Tualang honey supplement improves memory performance and hippocampal morphology in stressed ovariectomized rats. Acta Histochemica 2014c; 116: 79-88. https://doi.org/10.1016/j.acthis.2013.05.004 ##Ali AM, Hendawy AO. Bee honey as a potentially effective treatment for depression: a review of clinical and preclinical findings. JOJ Nurse Health Care 2018; 9: 555764. https://doi.org/10.19080/JOJNHC.2018.09.555764 ##Arabmoazzen S, Sarkaki A. Antidiabetic effect of honey feeding in noise induced hyperglycemic rat: involvement of oxidative stress. Iran J Basic Med Sci 2015; 18: 745. ##Arshad NA, Lin TS, Yahaya MF. Stingless bee honey reduces anxiety and improves memory of the metabolic disease-induced rats. CNS Neurol Disord Drug Targets 2020. https://doi.org/10.2174/1871527319666200117105133 ##Azman KF, Zakaria R, AbdAziz C, Othman Z, Al-Rahbi B. Tualang honey improves memory performance and decreases depressive-like behavior in rats exposed to loud noise stress. Noise Health 2015; 17: 83. https://doi.org/10.4103/1463-1741.153388 ##Azman KF, Zakaria R, Abdul Aziz CB, Othman Z. Tualang honey attenuates noise stress-induced memory deficits in aged rats. Oxid Med Cell Longev 2016; 2016. https://doi.org/10.1155/2016/1549158 ##Bakhtiarzadeh F, Nahavandi A, Goudarzi M, Shirvalilou S, Rakhshan K, Niknazar S. Axonal transport proteins and depressive like behavior, following chronic unpredictable mild stress in male rat. Physiol Behav 2018; 194: 9-14. https://doi.org/10.1016/j.physbeh.2018.04.029 ##Baluchnejadmojarad T, Roghani M, Kamran M, Karimi N. The effect of alpha-lipoic acid on learning and memory deficit in a rat model of temporal lobe epilepsy. Basic Clin Neurosci 2012; 3: 58-66. ##Belovicova K, Bogi E, Csatlosova K, Dubovicky M. Animal tests for anxiety-like and depression-like behavior in rats. Interdiscip Toxicol 2017; 10: 40-3. https://doi.org/10.1515/intox-2017-0006 ##Borges Filho C, Jesse CR, Donato F, Del Fabbro L, de Gomes MG, Goes AT, et al. Neurochemical factors associated with the antidepressant-like effect of flavonoid chrysin in chronically stressed mice. Eur J Pharmacol 2016; 791: 284-96. https://doi.org/10.1016/j.ejphar.2016.09.005 ##Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991; 82: 239-59. https://doi.org/10.1007/BF00308809 ##Casson RJ, Chidlow G, Ebneter A, Wood JP, Crowston J, Goldberg I. Translational neuroprotection research in glaucoma: a review of definitions and principles. Clin Exp Ophthalmol 2012; 40: 350-7. https://doi.org/10.1111/j.1442-9071.2011.02563.x ##Che Y, Zhou Z, Shu Y, Zhai C, Zhu Y, Gong S, et al. Chronic unpredictable stress impairs endogenous antioxidant defense in rat brain. Neurosci lett 2015; 584: 208-13. https://doi.org/10.1016/j.neulet.2014.10.031 ##Chen C, Zhang H, Xu H, Zheng Y, Wu T, Lian Y. Ginsenoside Rb1 ameliorates cisplatin-induced learning and memory impairments. J Ginseng Res 2019; 43: 499-507. https://doi.org/10.1016/j.jgr.2017.07.009 ##Chepulis LM, Starkey NJ, Waas JR, Molan PC. The effects of long-term honey, sucrose or sugar-free diets on memory and anxiety in rats. Physiol Behav 2009; 97: 359-68. https://doi.org/10.1016/j.physbeh.2009.03.001 ##Devan BD, Goad EH, Petri HL. Dissociation of hippocampal and striatal contributions to spatial navigation in the water maze. Neurobiol Learn Mem 1996; 66: 305-23. https://doi.org/10.1006/nlme.1996.0072 ##dos Santos Junior JG, do Monte FH, Blanco MM, Lanziotti VM, Maia FD, de Almeida Leal LK. Cognitive enhancement in aged rats after chronic administration of Equisetum arvense L. with demonstrated antioxidant properties in vitro. Pharmacol Biochem Behav 2005; 81: 593-600. https://doi.org/10.1016/j.pbb.2005.04.012 ##Espinosa-Garcia C, Sayeed I, Yousuf S, Atif F, Sergeeva EG, Neigh GN, et al. Stress primes microglial polarization after global ischemia: therapeutic potential of progesterone. Brain Behav Immun 2017; 66: 177-92. https://doi.org/10.1016/j.bbi.2017.06.012 ##Farajdokht F, Nahavandi A, Soleimani M. Effects of dalteparin on structure of hippocampal neurons of rats in chronic stress. Basic Clin Neurosci 2012; 3: 32-7. ##Finlay JM, Zigmond MJ, Abercrombie ED. Increased dopamine and norepinephrine release in medial prefrontal cortex induced by acute and chronic stress: effects of diazepam. Neuroscience 1995; 64: 619-28. https://doi.org/10.1016/0306-4522(94)00331-X ##Ganji A, Salehi I, Nazari M, Taheri M, Komaki A. Effects of Hypericum scabrum extract on learning and memory and oxidant/antioxidant status in rats fed a long-term high-fat diet. Metab Brain Dis 2017; 32: 1255-65. https://doi.org/10.1007/s11011-017-0022-4 ##Gheldof N, Engeseth NJ. Antioxidant capacity of honeys from various floral sources based on the determination of oxygen radical absorbance capacity and inhibition of in vitro lipoprotein oxidation in human serum samples. J Agric Food Chem 2002; 50: 3050-5. https://doi.org/10.1021/jf0114637 ##Grippo AJ, Sullivan NR, Damjanoska KJ, Crane JW, Carrasco GA, Shi J, et al. Chronic mild stress induces behavioral and physiological changes, and may alter serotonin 1A receptor function, in male and cycling female rats. Psychopharmacology 2005; 179: 769-80. https://doi.org/10.1007/s00213-004-2103-4 ##Guler A, Bakan A, Nisbet C, Yavuz O. Determination of important biochemical properties of honey to discriminate pure and adulterated honey with sucrose (Saccharum officinarum L.) syrup. Food Chem 2007; 105: 1119-25. https://doi.org/10.1016/j.foodchem.2007.02.024 ##Hu M, Zou W, Wang CY, Chen X, Tan HY, Zeng HY, et al. Hydrogen sulfide protects against chronic unpredictable mild stress-induced oxidative stress in hippocampus by upregulation of BDNF-TrkB pathway. Oxid Med Cell Longev 2016; 2016. https://doi.org/10.1155/2016/2153745 ##Ikeda-Douglas CJ, Zicker SC, Estrada J, Jewell DE, Milgram NW. Prior experience, antioxidants, and mitochondrial cofactors improve cognitive function in aged beagles. Vet Therapeut 2004; 5: 5-16. ##Jafari Anarkooli I, Barzegar Ganji H, Pourheidar M. The protective effects of insulin and natural honey against hippocampal cell death in streptozotocin-induced diabetic rats. J Diabetes Res 2014; 2014. https://doi.org/10.1155/2014/491571 ##Jesse CR, Donato F, Giacomeli R, Del Fabbro L, da Silva Antunes M, De Gomes MG, et al. Chronic unpredictable mild stress decreases BDNF and NGF levels and Na+, K+-ATPase activity in the hippocampus and prefrontal cortex of mice: Antidepressant effect of chrysin. Neuroscience 2015; 289: 367-380. https://doi.org/10.1016/j.neuroscience.2014.12.048 ##Jin P, Yu HL, Zhang F, Quan ZS. Antidepressant-like effects of oleoylethanolamide in a mouse model of chronic unpredictable mild stress. Pharmacol Biochem Behav 2015; 133: 146-54. https://doi.org/10.1016/j.pbb.2015.04.001 ##Jivad N, Zare-Hassanabadi N, Azizi M. Effect of combination of honey, saffron (Crocus sativus L.) and sedge (Cyperus rotundus L.) on cognitive dysfunction in patients with Alzheimer’s disease. Adv Herbal Med 2015; 1: 11-6. ##Kim EJ, Pellman B, Kim JJ. Stress effects on the hippocampus: a critical review. Learn Mem 2015; 22: 411-6. https://doi.org/10.1101/lm.037291.114 ##Kolosova NG, Shcheglova TV, Sergeeva SV, Loskutova LV. Long-term antioxidant supplementation attenuates oxidative stress markers and cognitive deficits in senescent-accelerated OXYS rats. Neurobiol Aging 2006; 27: 1289-97. https://doi.org/10.1016/j.neurobiolaging.2005.07.022 ##Krugers HJ, Lucassen P, Karst H, Joëls M. Chronic stress effects on hippocampal structure and synaptic function: relevance for depression and normalization by anti-glucocorticoid treatment. Front Synaptic Neurosci 2010; 2: 24. https://doi.org/10.3389/fnsyn.2010.00024 ##Latt HM, Matsushita H, Morino M, Koga Y, Michiue H, Nishiki T, et al. Oxytocin inhibits corticosterone-induced apoptosis in primary hippocampal neurons. Neuroscience 2018; 379: 383-9. https://doi.org/10.1016/j.neuroscience.2018.03.025##Lee AL, Ogle WO, Sapolsky RM. Stress and depression: possible links to neuron death in the hippocampus. Bipolar Disord 2002; 4: 117-28. https://doi.org/10.1034/j.1399-5618.2002.01144.x ##Lindau M, Almkvist O, Mohammed AH. Effects of stress on learning and memory. In: Stress: Concepts, cognition, emotion, and behavior. Academic Press, 2016, p. 153-160. https://doi.org/10.1016/B978-0-12-800951-2.00018-2 ##Liu D, Wang Z, Gao Z, Xie K, Zhang Q, Jiang H, et al. Effects of curcumin on learning and memory deficits, BDNF, and ERK protein expression in rats exposed to chronic unpredictable stress. Behav Brain Res 2014; 271: 116-21. https://doi.org/10.1016/j.bbr.2014.05.068 ##MacMaster FP, Kusumakar V. Hippocampal volume in early onset depression. BMC Med 2004; 2: 2. https://doi.org/10.1186/1741-7015-2-2 ##Mahmoodi-Khaledi E, Lozano-Sánchez J, Bakhouche A, Habibi-Rezaei M, Sadeghian I, Segura-Carretero A. Physicochemical properties and biological activities of honeys from different geographical and botanical origins in Iran. Eur Food Res Technol 2017; 243: 1019-30. https://doi.org/10.1007/s00217-016-2811-0 ##Manoli LP, Gamaro GD, Silveira PP, Dalmaz C. Effect of chronic variate stress on thiobarbituric-acid reactive species and on total radical-trapping potential in distinct regions of rat brain. Neurochem Res 2000; 25: 915-21. https://doi.org/10.1023/A:1007592022575 ##Marrocco I, Altieri F, Peluso I. Measurement and clinical significance of biomarkers of oxidative stress in humans. Oxid Med Cell Longev 2017; 2017. https://doi.org/10.1155/2017/6501046 ##Maurya S, Kushwaha AK, Singh S, Singh G. An overview on antioxidative potential of honey from different flora and geographical origins. Indian J Nat Prod Resour 2014; 5: 9-19. ##Mehrpouya S, Nahavandi A, Khojasteh F, Soleimani M, Ahmadi M, Barati M. Iron administration prevents BDNF decrease and depressive-like behavior following chronic stress. Brain Res 2015; 1596: 79-87. https://doi.org/10.1016/j.brainres.2014.10.057 ##Mehta V, Parashar A, Udayabanu M. Quercetin prevents chronic unpredictable stress induced behavioral dysfunction in mice by alleviating hippocampal oxidative and inflammatory stress. Physiol Behav 2017a; 171: 69-78. https://doi.org/10.1016/j.physbeh.2017.01.006 ##Mehta V, Singh TR, Udayabanu M. Quercetin ameliorates chronic unpredicted stress-induced behavioral dysfunction in male Swiss albino mice by modulating hippocampal insulin signaling pathway. Physiol Behav 2017b; 182: 10-6. https://doi.org/10.1016/j.physbeh.2017.09.019 ##Mohammadi HS, Goudarzi I, Lashkarbolouki T, Abrari K, Salmani ME. Chronic administration of quercetin prevent spatial learning and memory deficits provoked by chronic stress in rats. Behav Brain Res 2014; 270: 196-205. https://doi.org/10.1016/j.bbr.2014.05.015 ##Moloudian H, Abbasian S, Nassiri-Koopaei N, Tahmasbi MR, Alsadat Afzal G, Ahosseini MS, et al. Characterization and classification of iranian honey based on physicochemical properties and antioxidant activities, with chemometrics approach. Iran J Pharm Res 2018; 17: 708. ##Mora F, Segovia G, del Arco A, de Blas M, Garrido P. Stress, neurotransmitters, corticosterone and body-brain integration. Brain Res 2012; 1476: 71-85. https://doi.org/10.1016/j.brainres.2011.12.049 ##Morris RG. The watermaze. In: The Maze Book. New York: Springer, Humana Press 2015, p. 73-92. https://doi.org/10.1007/978-1-4939-2159-1_3 ##Najafi M, Shaseb E, Ghaffary S, Fakhrju A, Eteraf Oskouei T. Effects of chronic oral administration of natural honey on ischemia/reperfusion-induced arrhythmias in isolated rat heart. Iran J Basic Med Sci 2011; 14: 75-81. ##Natarajan R, Forrester L, Chiaia NL, Yamamoto BK. Chronic-stress-induced behavioral changes associated with subregion-selective serotonin cell death in the dorsal raphe. J Neurosci 2017; 37: 6214-23. https://doi.org/10.1523/JNEUROSCI.3781-16.2017 ##Noseworthy MD, Bray TM. Effect of oxidative stress on brain damage detected by MRI and in vivo 31P-NMR. Free Radic Biol Med 1998; 24: 942-51. https://doi.org/10.1016/S0891-5849(97)00383-3 ##Othman Z, Shafin N, Zakaria R, Hussain NH, Mohammad WM. Improvement in immediate memory after 16 weeks of tualang honey (Agro Mas) supplement in healthy postmenopausal women. Menopause 2011; 18: 1219-24. https://doi.org/10.1097/gme.0b013e31821e2044 ##Oyefuga OH, Ajani EO, Salau BA, Agboola F, Adebawo OO. Honey consumption and its anti-ageing potency in white Wister albino rats. Sch J Biol Sci 2012; 1: 15-9. ##Paxinos G, Watson C. The rat brain in stereotaxic coordinates: hard cover edition. Elsevier, 2006. ##Popović N, Stojiljković V, Pejić S, Todorović A, Pavlović I, Gavrilović L, et al. Modulation of hippocampal antioxidant defense system in chronically stressed rats by lithium. Oxid Med Cell Longev 2019; 2019. https://doi.org/10.1155/2019/8745376 ##Price RB, Duman R. Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model. Mol Psychiatry 2020; 25: 530-43. https://doi.org/10.1038/s41380-019-0615-x ##Rostamkhani F, Zardooz H, Zahediasl S, Farrokhi B. Comparison of the effects of acute and chronic psychological stress on metabolic features in rats. J Zhejiang Univ Sci B 2012; 13: 904-12. https://doi.org/10.1631/jzus.B1100383 ##Saad MA, Salam RM, Kenawy SA, Attia AS. Pinocembrin attenuates hippocampal inflammation, oxidative perturbations and apoptosis in a rat model of global cerebral ischemia reperfusion. Pharmacol Rep 2015; 67: 115-22. https://doi.org/10.1016/j.pharep.2014.08.014 ##Sadeghi M, Reisi P, Radahmadi M. The effects of CCK-8S on spatial memory and long-term potentiation at CA1 during induction of stress in rats. Iran J Basic Med Sci 2017; 20: 1368. ##Salim S. Oxidative stress and the central nervous system. J Pharmacol Exp Ther 2017; 360: 201-5. https://doi.org/10.1124/jpet.116.237503 ##Sapolsky RM. The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biol Psychiatry 2000; 48: 755-65. https://doi.org/10.1016/S0006-3223(00)00971-9 ##Schiavone S, Jaquet V, Trabace L, Krause KH. Severe life stress and oxidative stress in the brain: from animal models to human pathology. Antioxid Redox Signal 2013; 18: 1475-90. https://doi.org/10.1089/ars.2012.4720 ##Setti SE, Hunsberger HC, Reed MN. Alterations in hippocampal activity and Alzheimer’s disease. Transl Issues Psychol Sci 2017; 3: 348-56. https://doi.org/10.1037/tps0000124 ##Sheas MN, Rasool H, Rafique MN, Tariq MR, Muhammad A, Ali K. Exploring the potential of honey and curcumin as antidepressent. Punjab Univ J Zool 2019; 34: 89-95. https://doi.org/10.17582/journal.pujz/2019.34.1.89.95 ##Souza-Monteiro JR, Arrifano GP, Queiroz AI, Mello BS, Custódio CS, Macêdo DS, et al. Antidepressant and antiaging effects of acai (euterpe oleracea mart.) in mice. Oxid Med Cell Longev 2019; 2019. https://doi.org/10.1155/2019/3614960 ##Srivastava KK, Kumar R. Stress, oxidative injury and disease. Indian J Clin Biochem 2015; 30: 3-10. https://doi.org/10.1007/s12291-014-0441-5 ##Stemmelin J, Canolle B, Roudieres V, Labie C, Fournier J, Cohen C, et al. P. 2. d. 020 Saredutant (SR48968), a NK2 receptor antagonist, blocks chronic stress-induced decrease in neurogenesis in Balb/c mice. Eur Neuropsychopharmacol 2008: S356. https://doi.org/10.1016/S0924-977X(08)70502-9 ##Stemmelin J, Cohen C, Yalcin I, Keane P, Griebel G. Implication of β3-adrenoceptors in the antidepressant-like effects of amibegron using Adrb3 knockout mice in the chronic mild stress. Behav Brain Res 2010; 206: 310-2. https://doi.org/10.1016/j.bbr.2009.09.003 ##Surget A, Tanti A, Leonardo ED, Laugeray A, Rainer Q, Touma C, et al. Antidepressants recruit new neurons to improve stress response regulation. Mol Psychiatry 2011; 16: 1177-88. https://doi.org/10.1038/mp.2011.48 ##Takashima M, Ichihara K, Hirata Y. Neuroprotective effects of Brazilian green propolis on oxytosis/ferroptosis in mouse hippocampal HT22 cells. Food Chem Toxicol 2019; 132: 110669. https://doi.org/10.1016/j.fct.2019.110669 ##Takuma K, Mizoguchi H, Funatsu Y, Kitahara Y, Ibi D, Kamei H, et al. Placental extract improves hippocampal neuronal loss and fear memory impairment resulting from chronic restraint stress in ovariectomized mice. J Pharmacol Sci 2012; 120: 89-97. https://doi.org/10.1254/jphs.12115FP ##Tyrtyshnaia AA, Manzhulo IV, Konovalova SP, Zagliadkina AA. Neuropathic pain causes a decrease in the dendritic tree complexity of hippocampal CA3 pyramidal neurons. Cells Tissues Organs 2019; 208: 89-100. https://doi.org/10.1159/000506812 ##Ulrich-Lai YM, Figueiredo HF, Ostrander MM, Choi DC, Engeland WC, Herman JP. Chronic stress induces adrenal hyperplasia and hypertrophy in a subregion-specific manner. Am J Physiol Endocrinol Metab 2006; 291: E965-73. https://doi.org/10.1152/ajpendo.00070.2006 ##van Velzen LS, Wijdeveld M, Black CN, van Tol MJ, van der Wee NJ, et al. Oxidative stress and brain morphology in individuals with depression, anxiety and healthy controls. Prog Neuropsychopharmacol Biol Psychiatry 2017; 76: 140-4. https://doi.org/10.1016/j.pnpbp.2017.02.017 ##Wang W, Zheng L, Xu L, Tu J, Gu X. Pinocembrin mitigates depressive-like behaviors induced by chronic unpredictable mild stress through ameliorating neuroinflammation and apoptosis. Mol Med 2020; 26: 1-11. https://doi.org/10.1186/s10020-020-00179-x ##Wang X, Michaelis EK. Selective neuronal vulnerability to oxidative stress in the brain. Front Aging Neurosci 2010; 2: 12. https://doi.org/10.3389/fnagi.2010.00012 ##Wang X, Sankarapandian K, Cheng Y, Woo SO, Kwon HW, Perumalsamy H, et al. Relationship between total phenolic contents and biological properties of propolis from 20 different regions in South Korea. BMC Compl Alternative Med 2016; 16: 65. https://doi.org/10.1186/s12906-016-1043-y ##Willner P. The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiol Stress 2017; 6: 78-93. https://doi.org/10.1016/j.ynstr.2016.08.002 ##Willner P. Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology 1997; 134: 319-29. https://doi.org/10.1007/s002130050456 ##Wu GF, Ren S, Tang RY, Xu C, Zhou JQ, Lin SM, et al. Antidepressant effect of taurine in chronic unpredictable mild stress-induced depressive rats. Sci Rep 2017; 7: 1-4. https://doi.org/10.1038/s41598-017-05051-3 ##Xu B, Lang LM, Lian S, Guo JR, Wang JF, Yang HM, et al. Oxidation stress-mediated MAPK signaling pathway activation induces neuronal loss in the CA1 and CA3 regions of the hippocampus of mice following chronic cold exposure. Brain Sci 2019; 9: 273. https://doi.org/10.3390/brainsci9100273 ##Xue MQ, Quan HF, Wang R, Zhao XX, Yan L, Zhu YF, et al. Mitigation of chronic unpredictable stress-induced cognitive deficits in mice by Lycium barbarum L (Solanaceae) polysaccharides. Trop J Pharm Res 2017; 16: 1893-901. https://doi.org/10.4314/tjpr.v16i8.20 ##Yang XH, Song SQ, Xu Y. Resveratrol ameliorates chronic unpredictable mild stress-induced depression-like behavior: involvement of the HPA axis, inflammatory markers, BDNF, and Wnt/β-catenin pathway in rats. Neuropsych Dis Treat 2017; 13: 2727. https://doi.org/10.2147/NDT.S150028 ##Yaribeygi H, Panahi Y, Sahraei H, Johnston TP, Sahebkar A. The impact of stress on body function: A review. EXCLI J 2017; 16: 1057. ##Yazdi A, Doostmohammadi M, Majarshin FP, Beheshti S. Betahistine, prevents kindling, ameliorates the behavioral comorbidities and neurodegeneration induced by pentylenetetrazole. Epilepsy Behav 2020; 105: 106956. https://doi.org/10.1016/j.yebeh.2020.106956 ##Zhang H, Wei M, Sun Q, Yang T, Lu X, Feng X, et al. Lycopene ameliorates chronic stress-induced hippocampal injury and subsequent learning and memory dysfunction through inhibiting ROS/JNK signaling pathway in rats. Food Chem Toxicol 2020; 111688. https://doi.org/10.1016/j.fct.2020.111688## ##

Protective effect of honey on learning and memory impairment, depression and neurodegeneration induced by chronic unpredictable mild stress 2 2 Introduction: Chronic stress, which has been prevalent in human life, induce structural changes in the hippocampus. Depression and impairment of memory are serious comorbidities of chronic stress. In this study, we evaluated the impact of an Iranian honey pretreatment on memory deficit, depression and the hippocampal neuronal loss in the chronic unpredictable mild stress (CUMS) model. Methods: Adult male Wistar rats were divided into the control groups that received water or honey (0.2 or 2g/kg) and CUMS groups that subjected different, randomly and unpredictable mild stressors for 4 weeks. Ten days before starting the CUMS procedures, the animals received honey (0.2 or 2g/kg, daily, orally), which was continued until sacrificing. Morris water maze and sucrose performance tests were used to evaluate the spatial learning and memory and depressive-like behavior in the animals respectively. Hippocampus and whole brain samples were collected for further biochemical and histological analysis. Results: Honey reversed the depression-like behavior and ameliorated the spatial memory deficit induced by CUMS. Also, honey decreased cell death in the hippocampus and reduced the malondialdehyde level in treated animals. Conclusion: These results revealed that honey diminished learning and memory deficits and depression in chronic stress conditions. 21 35 2020/04/242020/06/152020/07/22 1399/5/1 2020/07/252020/12/12020/10/27 1399/8/6 Asiye Rafiee Sardooi Asiye Rafiee Sardooi Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Iran asiye_rafiee@yahoo.com Parham Reisi Parham Reisi Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Iran parhamzh@gmail.com Azadeh Yazdi Azadeh Yazdi Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Iran a.yazdi@mail.mui.ac.ir Honey Chronic mild stress Learning and memory Neuronal loss Oxidative stress. Abdulmajeed W I, Sulieman H B, Zubayr M O, Imam A, Amin A, Biliaminu S A, et al. Honey prevents neurobehavioural deficit and oxidative stress induced by lead acetate exposure in male wistar rats-a preliminary study. Metabolic brain disease 2016; 31: 37-44.##Adli D S H. Morphometric Study of Hippocampal CA1 Pyramidal Neurons after Tualang Honey Administration. Malaysian Journal of Microscopy 2018; 14.##Aĭrapetiants M, Levshina I, Guliaeva N. Therapeutic action of an antioxidant in chronic emotional-pain stress in the rat. Zhurnal vysshei nervnoi deiatelnosti imeni IP Pavlova 1986; 36: 554-560.##Akanmu M A, Olowookere T A, Atunwa S A, Ibrahim B O, Lamidi O F, Adams P A, et al. Neuropharmacological effects of Nigerian honey in mice. African Journal of Traditional, Complementary and Alternative Medicines 2011; 8.##Akouchekian S, Omranifard V, Maracy M R, Pedram A, Zefreh A A. Efficacy of herbal combination of sedge, saffron, and Astragalus honey on major neurocognitive disorder. Journal of research in medical sciences: the official journal of Isfahan University of Medical Sciences 2018; 23.##Al-Rahbi B, Zakaria R, Othman Z, Hassan A, Ahmad A H. Enhancement of BDNF concentration and restoration of the hypothalamic-pituitary-adrenal axis accompany reduced depressive-like behaviour in stressed ovariectomised rats treated with either Tualang honey or estrogen. The Scientific World Journal 2014a; 2014.##Al-Rahbi B, Zakaria R, Othman Z, Hassan A, Ahmad A H. Protective effects of Tualang honey against oxidative stress and anxiety-like behaviour in stressed ovariectomized rats. International scholarly research notices 2014b; 2014.##Al-Rahbi B, Zakaria R, Othman Z, Hassan A, Ismail Z I M, Muthuraju S. Tualang honey supplement improves memory performance and hippocampal morphology in stressed ovariectomized rats. Acta histochemica 2014c; 116: 79-88.##Ali A M, Hendawy A O. Bee honey as a potentially effective treat‐ment for depression: a review of clinical and preclinical findings. JOJ Nurse Health Care 2018; 9: 555764.##Arabmoazzen S, Sarkaki A. Antidiabetic effect of honey feeding in noise induced hyperglycemic rat: involvement of oxidative stress. Iranian journal of basic medical sciences 2015; 18: 745.##Arshad N A, Lin T S, Yahaya M F. Stingless Bee Honey Reduces Anxiety and Improves Memory of the Metabolic Disease-inDuced Rats. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders) 2020.##Azman K F, Zakaria R, AbdAziz C, Othman Z, Al-Rahbi B. Tualang honey improves memory performance and decreases depressive-like behavior in rats exposed to loud noise stress. Noise & health 2015; 17: 83.##Azman K F, Zakaria R, Abdul Aziz C B, Othman Z. Tualang honey attenuates noise stress-induced memory deficits in aged rats. Oxidative medicine and cellular longevity 2016; 2016.##Bakhtiarzadeh F, Nahavandi A, Goudarzi M, Shirvalilou S, Rakhshan K, Niknazar S. Axonal transport proteins and depressive like behavior, following Chronic Unpredictable Mild Stress in male rat. Physiology & behavior 2018; 194: 9-14.##Baluchnejadmojarad T, Roghani M, Kamran M, Karimi N. The Effect of Alpha-Lipoic Acid on Learning and Memory Deficit in a Rat Model of Temporal Lobe Epilepsy. Basic and Clinical Neuroscience 2012; 3: 58-66.##Belovicova K, Bogi E, Csatlosova K, Dubovicky M. Animal tests for anxiety-like and depression-like behavior in rats. Interdisciplinary toxicology 2017; 10: 40-43.##Borges Filho C, Jesse C R, Donato F, Del Fabbro L, de Gomes M G, Goes A T R, et al. Neurochemical factors associated with the antidepressant-like effect of flavonoid chrysin in chronically stressed mice. European journal of pharmacology 2016; 791: 284-296.##Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta neuropathologica 1991; 82: 239-259.##Casson R J, Chidlow G, Ebneter A, Wood J P, Crowston J, Goldberg I. Translational neuroprotection research in glaucoma: a review of definitions and principles. Clinical & experimental ophthalmology 2012; 40: 350-357.##Che Y, Zhou Z, Shu Y, Zhai C, Zhu Y, Gong S, et al. Chronic unpredictable stress impairs endogenous antioxidant defense in rat brain. Neuroscience letters 2015; 584: 208-213.##Chen C, Zhang H, Xu H, Zheng Y, Wu T, Lian Y. Ginsenoside Rb1 ameliorates cisplatin-induced learning and memory impairments. Journal of ginseng research 2019; 43: 499-507.##Chepulis L M, Starkey N J, Waas J R, Molan P C. The effects of long-term honey, sucrose or sugar-free diets on memory and anxiety in rats. Physiology & behavior 2009; 97: 359-368.##Devan B D, Goad E H, Petri H L. Dissociation of hippocampal and striatal contributions to spatial navigation in the water maze. Neurobiology of learning and memory 1996; 66: 305-323.##dos Santos Junior J G, do Monte F H M, Blanco M M, Lanziotti V M d N B, Maia F D, de Almeida Leal L K. Cognitive enhancement in aged rats after chronic administration of Equisetum arvense L. with demonstrated antioxidant properties in vitro. Pharmacology Biochemistry and Behavior 2005; 81: 593-600.##Espinosa-Garcia C, Sayeed I, Yousuf S, Atif F, Sergeeva E G, Neigh G N, et al. Stress primes microglial polarization after global ischemia: therapeutic potential of progesterone. Brain, behavior, and immunity 2017; 66: 177-192.##Farajdokht F, Nahavandi A, Soleimani M. Effects of dalteparin on structure of hippocampal neurons of rats in chronic stress. Basic and Clinical Neuroscience 2012; 3: 32-37.##Finlay J, Zigmond M, Abercrombie E. Increased dopamine and norepinephrine release in medial prefrontal cortex induced by acute and chronic stress: effects of diazepam. Neuroscience 1995; 64: 619-628.##Ganji A, Salehi I, Nazari M, Taheri M, Komaki A. Effects of Hypericum scabrum extract on learning and memory and oxidant/antioxidant status in rats fed a long-term high-fat diet. Metabolic brain disease 2017; 32: 1255-1265.##Gheldof N, Engeseth N J. Antioxidant capacity of honeys from various floral sources based on the determination of oxygen radical absorbance capacity and inhibition of in vitro lipoprotein oxidation in human serum samples. Journal of agricultural and food chemistry 2002; 50: 3050-3055.##Grippo A J, Sullivan N R, Damjanoska K J, Crane J W, Carrasco G A, Shi J, et al. Chronic mild stress induces behavioral and physiological changes, and may alter serotonin 1A receptor function, in male and cycling female rats. Psychopharmacology 2005; 179: 769-780.##Guler A, Bakan A, Nisbet C, Yavuz O. Determination of important biochemical properties of honey to discriminate pure and adulterated honey with sucrose (Saccharum officinarum L.) syrup. Food chemistry 2007; 105: 1119-1125.##Hu M, Zou W, Wang C-Y, Chen X, Tan H-Y, Zeng H-Y, et al. Hydrogen sulfide protects against chronic unpredictable mild stress-induced oxidative stress in hippocampus by upregulation of BDNF-TrkB pathway. Oxidative medicine and cellular longevity 2016; 2016.##Ikeda-Douglas C, Zicker S, Estrada J, Jewell D, Milgram N. Prior experience, antioxidants, and mitochondrial cofactors improve cognitive function in aged beagles. Veterinary therapeutics: research in applied veterinary medicine 2004; 5: 5-16.##Jafari Anarkooli I, Barzegar Ganji H, Pourheidar M. The protective effects of insulin and natural honey against hippocampal cell death in streptozotocin-induced diabetic rats. Journal of diabetes research 2014; 2014.##Jesse C, Donato F, Giacomeli R, Del Fabbro L, da Silva Antunes M, De Gomes M, et al. Chronic unpredictable mild stress decreases BDNF and NGF levels and Na+, K+-ATPase activity in the hippocampus and prefrontal cortex of mice: Antidepressant effect of chrysin. Neuroscience 2015; 289: 367-380.##Jin P, Yu H-L, Zhang F, Quan Z-S. Antidepressant-like effects of oleoylethanolamide in a mouse model of chronic unpredictable mild stress. Pharmacology Biochemistry and Behavior 2015; 133: 146-154.##Jivad N, Zare-Hassanabadi N, Azizi M. Effect of combination of honey, saffron (Crocus sativus L.) and sedge (Cyperus rotundus L.) on cognitive dysfunction in patients with Alzheimer's disease. Advanced Herbal Medicine 2015; 1: 11-16.##Kim E J, Pellman B, Kim J J. Stress effects on the hippocampus: a critical review. Learning & memory 2015; 22: 411-416.##Kolosova N, Shcheglova T, Sergeeva S, Loskutova L. Long-term antioxidant supplementation attenuates oxidative stress markers and cognitive deficits in senescent-accelerated OXYS rats. Neurobiology of aging 2006; 27: 1289-1297.##Krugers H J, Lucassen P, Karst H, Joëls M. Chronic stress effects on hippocampal structure and synaptic function: relevance for depression and normalization by anti-glucocorticoid treatment. Frontiers in synaptic neuroscience 2010; 2: 24.##Latt H M, Matsushita H, Morino M, Koga Y, Michiue H, Nishiki T, et al. Oxytocin inhibits corticosterone-induced apoptosis in primary hippocampal neurons. Neuroscience 2018; 379: 383-389.##Lee A L, Ogle W O, Sapolsky R M. Stress and depression: possible links to neuron death in the hippocampus. Bipolar disorders 2002; 4: 117-128.##Lindau M, Almkvist O, Mohammed A. Effects of stress on learning and memory. Stress: Concepts, cognition, emotion, and behavior: Elsevier, 2016: 153-160.##Liu D, Wang Z, Gao Z, Xie K, Zhang Q, Jiang H, et al. Effects of curcumin on learning and memory deficits, BDNF, and ERK protein expression in rats exposed to chronic unpredictable stress. Behavioural brain research 2014; 271: 116-121.##MacMaster F P, Kusumakar V. Hippocampal volume in early onset depression. BMC medicine 2004; 2: 2.##Mahmoodi-Khaledi E, Lozano-Sánchez J, Bakhouche A, Habibi-Rezaei M, Sadeghian I, Segura-Carretero A. Physicochemical properties and biological activities of honeys from different geographical and botanical origins in Iran. European Food Research and Technology 2017; 243: 1019-1030.##Manoli L, Gamaro G, Silveira P, Dalmaz C. Effect of chronic variate stress on thiobarbituric-acid reactive species and on total radical-trapping potential in distinct regions of rat brain. Neurochemical research 2000; 25: 915-921.##Marrocco I, Altieri F, Peluso I. Measurement and clinical significance of biomarkers of oxidative stress in humans. Oxidative medicine and cellular longevity 2017; 2017.##Maurya S, Kushwaha A K, Singh S, Singh G. An overview on antioxidative potential of honey from different flora and geographical origins. 2014.##Mehrpouya S, Nahavandi A, Khojasteh F, Soleimani M, Ahmadi M, Barati M. Iron administration prevents BDNF decrease and depressive-like behavior following chronic stress. Brain research 2015; 1596: 79-87.##Mehta V, Parashar A, Udayabanu M. Quercetin prevents chronic unpredictable stress induced behavioral dysfunction in mice by alleviating hippocampal oxidative and inflammatory stress. Physiology & behavior 2017a; 171: 69-78.##Mehta V, Singh T R, Udayabanu M. Quercetin ameliorates chronic unpredicted stress-induced behavioral dysfunction in male Swiss albino mice by modulating hippocampal insulin signaling pathway. Physiology & behavior 2017b; 182: 10-16.##Mohammadi H S, Goudarzi I, Lashkarbolouki T, Abrari K, Salmani M E. Chronic administration of quercetin prevent spatial learning and memory deficits provoked by chronic stress in rats. Behavioural brain research 2014; 270: 196-205.##Moloudian H, Abbasian S, Nassiri-Koopaei N, Tahmasbi M R, alsadat Afzal G, Ahosseini M S, et al. Characterization and Classification of Iranian Honey Based on Physicochemical Properties and Antioxidant Activities, with Chemometrics Approach. Iranian journal of pharmaceutical research: IJPR 2018; 17: 708.##Mora F, Segovia G, del Arco A, de Blas M, Garrido P. Stress, neurotransmitters, corticosterone and body–brain integration. Brain research 2012; 1476: 71-85.##Morris R G. The watermaze. The Maze Book: Springer, 2015: 73-92.##Najafi M, Shaseb E, Ghaffary S, Fakhrju A, Eteraf Oskouei T. Effects of chronic oral administration of natural honey on ischemia/reperfusion-induced arrhythmias in isolated rat heart. Iranian Journal of Basic Medical Sciences 2011; 14: 75-81.##Natarajan R, Forrester L, Chiaia N L, Yamamoto B K. Chronic-stress-induced behavioral changes associated with subregion-selective serotonin cell death in the dorsal raphe. Journal of Neuroscience 2017; 37: 6214-6223.##Noseworthy M D, Bray T M. Effect of oxidative stress on brain damage detected by MRI and in vivo 31P-NMR. Free radical biology and medicine 1998; 24: 942-951.##Othman Z, Shafin N, Zakaria R, Hussain N H N, Mohammad W M Z W. Improvement in immediate memory after 16 weeks of tualang honey (Agro Mas) supplement in healthy postmenopausal women. Menopause 2011; 18: 1219-1224.##Oyefuga O, Ajani E, Salau B, Agboola F, Adebawo O. Honey consumption and its anti-ageing potency in white Wister albino rats. Sch J Biol Sci 2012; 1: 15-19.##Paxinos G, Watson C. The rat brain in stereotaxic coordinates: hard cover edition: Elsevier, 2006.##Popović N, Stojiljković V, Pejić S, Todorović A, Pavlović I, Gavrilović L, et al. Modulation of hippocampal antioxidant defense system in chronically stressed rats by lithium. Oxidative medicine and cellular longevity 2019; 2019.##Price R B, Duman R. Neuroplasticity in cognitive and psychological mechanisms of depression: An integrative model. Molecular psychiatry 2019: 1-14.##Rostamkhani F, Zardooz H, Zahediasl S, Farrokhi B. Comparison of the effects of acute and chronic psychological stress on metabolic features in rats. Journal of Zhejiang university science B 2012; 13: 904-912.##Saad M A, Salam R M A, Kenawy S A, Attia A S. Pinocembrin attenuates hippocampal inflammation, oxidative perturbations and apoptosis in a rat model of global cerebral ischemia reperfusion. Pharmacological Reports 2015; 67: 115-122.##Sadeghi M, Reisi P, Radahmadi M. The effects of CCK-8S on spatial memory and long-term potentiation at CA1 during induction of stress in rats. Iranian journal of basic medical sciences 2017; 20: 1368.##Salim S. Oxidative stress and the central nervous system. Journal of Pharmacology and Experimental Therapeutics 2017; 360: 201-205.##Sapolsky R M. The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death. Biological psychiatry 2000; 48: 755-765.##Schiavone S, Jaquet V, Trabace L, Krause K-H. Severe life stress and oxidative stress in the brain: from animal models to human pathology. Antioxidants & redox signaling 2013; 18: 1475-1490.##Setti S E, Hunsberger H C, Reed M N. Alterations in hippocampal activity and Alzheimer’s disease. Translational issues in psychological science 2017; 3: 348.##Sheas M N, Rasool H, Rafique M N, Tariq M R, Muhammad A, Ali K. Exploring the Potential of Honey and Curcumin as Antidepressent. Punjab University Journal of Zoology 2019; 34: 89-95.##Souza-Monteiro J R, Arrifano G P, Queiroz A I D, Mello B S, Custódio C S, Macêdo D S, et al. Antidepressant and antiaging effects of acai (euterpe oleracea mart.) in mice. Oxidative medicine and cellular longevity 2019; 2019.##Srivastava K K, Kumar R. Stress, oxidative injury and disease. Indian Journal of Clinical Biochemistry 2015; 30: 3-10.##Stemmelin J, Canolle B, Roudieres V, Labie C, Fournier J, Cohen C, et al. P. 2. d. 020 Saredutant (SR48968), a NK2 receptor antagonist, blocks chronic stress-induced decrease in neurogenesis in Balb/c mice. European Neuropsychopharmacology 2008: S356.##Stemmelin J, Cohen C, Yalcin I, Keane P, Griebel G. Implication of β3-adrenoceptors in the antidepressant-like effects of amibegron using Adrb3 knockout mice in the chronic mild stress. Behavioural brain research 2010; 206: 310-312.##Surget A, Tanti A, Leonardo E, Laugeray A, Rainer Q, Touma C, et al. Antidepressants recruit new neurons to improve stress response regulation. Molecular psychiatry 2011; 16: 1177-1188.##Takashima M, Ichihara K, Hirata Y. Neuroprotective effects of Brazilian green propolis on oxytosis/ferroptosis in mouse hippocampal HT22 cells. Food and Chemical Toxicology 2019; 132: 110669.##Takuma K, Mizoguchi H, Funatsu Y, Kitahara Y, Ibi D, Kamei H, et al. Placental extract improves hippocampal neuronal loss and fear memory impairment resulting from chronic restraint stress in ovariectomized mice. Journal of pharmacological sciences 2012; 120: 89-97.##Tyrtyshnaia A A, Manzhulo I V, Konovalova S P, Zagliadkina A A. Neuropathic Pain Causes a Decrease in the Dendritic Tree Complexity of Hippocampal CA3 Pyramidal Neurons. Cells Tissues Organs 2019; 208: 89-100.##Ulrich-Lai Y M, Figueiredo H F, Ostrander M M, Choi D C, Engeland W C, Herman J P. Chronic stress induces adrenal hyperplasia and hypertrophy in a subregion-specific manner. American journal of physiology-endocrinology and metabolism 2006; 291: E965-E973.##van Velzen L S, Wijdeveld M, Black C N, van Tol M-J, van der Wee N J, Veltman D J, et al. Oxidative stress and brain morphology in individuals with depression, anxiety and healthy controls. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2017; 76: 140-144.##Wang W, Zheng L, Xu L, Tu J, Gu X. Pinocembrin mitigates depressive-like behaviors induced by chronic unpredictable mild stress through ameliorating neuroinflammation and apoptosis. Molecular Medicine 2020; 26: 1-11.##Wang X, Michaelis E K. Selective neuronal vulnerability to oxidative stress in the brain. Frontiers in aging neuroscience 2010; 2: 12.##Wang X, Sankarapandian K, Cheng Y, Woo S O, Kwon H W, Perumalsamy H, et al. Relationship between total phenolic contents and biological properties of propolis from 20 different regions in South Korea. BMC complementary and alternative medicine 2016; 16: 65.##Willner P. The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiology of stress 2017; 6: 78-93.##Willner P. Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology 1997; 134: 319-329.##Wu G-F, Ren S, Tang R-Y, Xu C, Zhou J-Q, Lin S-M, et al. Antidepressant effect of taurine in chronic unpredictable mild stress-induced depressive rats. Scientific reports 2017; 7: 4989.##Xu B, Lang L-M, Lian S, Guo J-R, Wang J-F, Yang H-M, et al. Oxidation Stress-Mediated MAPK Signaling Pathway Activation Induces Neuronal Loss in the CA1 and CA3 Regions of the Hippocampus of Mice Following Chronic Cold Exposure. Brain Sciences 2019; 9: 273.##Xue M-Q, Quan H-F, Wang R, Zhao X-X, Yan L, Zhu Y-F, et al. Mitigation of chronic unpredictable stress–induced cognitive deficits in mice by Lycium barbarum L (Solanaceae) polysaccharides. Tropical Journal of Pharmaceutical Research 2017; 16: 1893-1901.##Yang X-h, Song S-Q, Xu Y. Resveratrol ameliorates chronic unpredictable mild stress-induced depression-like behavior: involvement of the HPA axis, inflammatory markers, BDNF, and Wnt/β-catenin pathway in rats. Neuropsychiatric disease and treatment 2017; 13: 2727.##Yaribeygi H, Panahi Y, Sahraei H, Johnston T P, Sahebkar A. The impact of stress on body function: A review. EXCLI journal 2017; 16: 1057.##Yazdi A, Doostmohammadi M, Majarshin F P, Beheshti S. Betahistine, prevents kindling, ameliorates the behavioral comorbidities and neurodegeneration induced by pentylenetetrazole. Epilepsy & Behavior 2020; 105: 106956.##Zhang H, Wei M, Sun Q, Yang T, Lu X, Feng X, et al. Lycopene ameliorates chronic stress-induced hippocampal injury and subsequent learning and memory dysfunction through inhibiting ROS/JNK signaling pathway in rats. Food and Chemical Toxicology 2020: 111688.## ##

Anticonvulsant effect of acute curcumin nanoparticle on pentylenetetrazole-induced seizures in mice: non-involvement of JNK restoration 2 2 Introduction: Although several animal studies have indicated the antiepileptic effect for curcumin, there are reports stating the null antiepileptic effect of this substance. This inconsistency might be due to the low bioavailability of curcumin. Therefore, the current study aimed to assess the effect of oral bovine serum albumin (BSA)-based nanocurcumin on seizure caused by pentylenetetrazol (PTZ) in mice. Furthermore, due to the suggested involvement of JNK signaling in seizure pathology, the hippocampal pattern of JNK phosphorylation (activation) was evaluated. Methods: BSA based nanocurcumin was administered at doses of 50 and 100mg/kg oral gavage to male NMRI mice, one hour before PTZ administration. Intravenous PTZ paradigm was used to determine the threshold dose of PTZ to induce clonic seizures, while the intraperitoneal PTZ paradigm was applied to evaluate the latency for appearance of generalized clonus. Upon completion of intraperitoneal PTZ paradigm experiments, the hippocampi were removed and Western blot analysis was performed to determine the phosphorylated and total forms of JNK. Results: The results indicated that BSA-based nanocurcumin at the doses of 50 and 100mg/kg could significantly increase the threshold and latency of clonic seizure, which was a significant superior effect compared to natural curcumin. PTZ significantly increased the level of hippocampal JNK phosphorylation, but pretreatment of nanocurcumin did not modify this effect. Conclusion: The present study shows that converting curcumin to BSA-based nanocurcumin can increase its antiepileptic effect. Furthermore, the antiepileptic effect of nanocurcumin was not associated with a modification in PTZ-induced hippocampal JNK hyper activation. 36 46 2020/04/242020/06/152020/07/222020/07/8 1399/4/18 2020/07/252020/12/12020/10/272020/10/27 1399/8/6 Leila Moezi Leila Moezi Nanobiology and Nanomedicine Research Centre, Shiraz University of Medical sciences, Shiraz, Iran Iran moezil@sums.ac.ir Nahid Ashjazadeh Nahid Ashjazadeh Clinical Neurology Research Center and Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran Iran Ashjazn@sums.ac.ir Shirin Rezapanah Shirin Rezapanah Clinical Neurology Research Center and Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran Iran shirin.rezapanah@gmail.com Fatema Pirsalami Fatema Pirsalami Clinical Neurology Research Center and Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran Iran pirsalamif@sums.ac.ir Zahra Esmaeili Zahra Esmaeili Nanobiology and Nanomedicine Research Centre, Shiraz University of Medical sciences, Shiraz, Iran Iran zesmaili1370@gmail.com Roksana SoukhakLari Roksana SoukhakLari Shiraz Neuroscience Research Centre, Shiraz University of Medical sciences, Shiraz, Iran Iran roxana.sookhak@yahoo.com Maryam Moosavi Maryam Moosavi Nanobiology and Nanomedicine Research Centre, Shiraz University of Medical sciences, Shiraz, Iran Iran marmoosavi@sums.ac.ir Curcumin Nanoparticle Seizure Hippocampus JNK Pentylenetetrazol. Aggarwal BB, Sundaram C, Malani N, Ichikawa H. Curcumin: the Indian solid gold. In: The molecular targets and therapeutic uses of curcumin in health and disease. Boston: Springer, 2007, p.1-75.https://doi.org/10.1007/978-0-387-46401-5_1##Agarwal NB, Jain S, Nagpal D, Agarwal NK, Mediratta PK, Sharma KK. Liposomal formulation of curcumin attenuates seizures in different experimental models of epilepsy in mice. Fund Clin Pharmacol 2013; 27: 169-72. https://doi.org/10.1111/j.1472-8206.2011.01002.x##Akula KK, Kulkarni SK. Effect of curcumin against pentylenetetrazol-induced seizure threshold in mice: Possible involvement of adenosine A1 receptors. Phytother Res 2014; 28: 714-21. https://doi.org/10.1002/ptr.5048 ##Amiri E, Ghasemi R, Moosavi M. Agmatine protects against 6-ohda-induced apoptosis, and erk and akt/gsk disruption in sh-sy5y cells. Cell Mol Neurobiol 2016; 36: 829-838. https://doi.org/10.1007/s10571-015-0266-7##Ben J, de Oliveira PA, Gonçalves FM, Peres TV, Matheus FC, Hoeller AA, et al. Effects of pentylenetetrazole kindling on mitogen-activated protein kinases levels in neocortex and hippocampus of mice. Neurochem Res 2014; 39: 2492-500. https://doi.org/10.1007/s11064-014-1453-5 ##Buckmaster PS, Wen X, Toyoda I, Gulland FM, Van Bonn W. Hippocampal neuropathology of domoic acid-induced epilepsy in california sea lions (zalophus californianus). J Comp Neurol 2014; 522: 1691-706. https://doi.org/10.1002/cne.23509 ##Choudhary KM, Mishra A, Poroikov VV, Goel RK. Ameliorative effect of curcumin on seizure severity, depression like behavior, learning and memory deficit in post-pentylenetetrazole-kindled mice. Eur J Pharmacol 2013; 704: 33-40. https://doi.org/10.1016/j.ejphar.2013.02.012 ##Cole-Edwards KK, Musto AE, Bazan NG. c-Jun N-terminal kinase activation responses induced by hippocampal kindling are mediated by reactive astrocytes. J Neurosci 2006; 26: 8295-304.https://doi.org/10.1523/JNEUROSCI.1986-05.2006 ##Collett GP, Campbell FC. Curcumin induces c-jun n-terminal kinase-dependent apoptosis in hct116 human colon cancer cells. Carcinogenesis 2004; 25: 2183-9. https://doi.org/10.1093/carcin/bgh233##Delfiya DA, Thangavel K, Amirtham D. Preparation of curcumin loaded egg albumin nanoparticles using acetone and optimization of desolvation process. Protein J 2016; 35: 124-35.https://doi.org/10.1007/s10930-016-9652-3 ##Dhir A. Curcumin in epilepsy disorders. Phytother Res 2018; 32: 1865-75. https://doi.org/10.1002/ptr.6125 ##Drion CM, Borm LE, Kooijman L, Aronica E, Wadman WJ, Hartog AF, et al. Effects of rapamycin and curcumin treatment on the development of epilepsy after electrically induced status epilepticus in rats. Epilepsia 2016; 57: 688-97. https://doi.org/10.1111/epi.13345 ##Duncan JS, Sander JW, Sisodiya SM, Walker MC. Adult epilepsy. Lancet 2006; 367: 1087-100.https://doi.org/10.1016/S0140-6736(06)68477-8 ##Flora G, Gupta D, Tiwari A. Nanocurcumin: a promising therapeutic advancement over native curcumin. Crit Rev Ther Drug Carrier Syst 2013; 30: 331-68. https://doi.org/10.1615/CritRevTherDrugCarrierSyst.2013007236 ##Geng S, Wang S, Zhu W, Xie C, Li X, Wu J, et al. Curcumin suppresses JNK pathway to attenuate BPA-induced insulin resistance in LO2 cells. Biomed Pharmacother 2018; 97: 1538-43.https://doi.org/10.1016/j.biopha.2017.11.069 ##Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as “curecumin”: from kitchen to clinic. Biochem Phar-macol 2008; 75: 787-809. https://doi.org/10.1016/j.bcp.2007.08.016 ##Hashemian M, Anissian D, Ghasemi-Kasman M, Akbari A, Khalili-Fomeshi M, Ghasemi S, et al. Curcumin-loaded chitosan-alginate-STPP nanoparticles ameliorate memory deficits and reduce glial activation in pentylenetetrazol-induced kindling model of epilepsy. Prog Neuropsychopharmacol Biol Psychiatry 2017; 79: 462-71. https://doi.org/10.1016/j.pnpbp.2017.07.025 ##Hsieh CL, Lin JJ, Chiang SY, Su SY, Tang NY, Lin GG, et al. Gastrodia elata modulated activator protein 1 via c-Jun N-terminal kinase signaling pathway in kainic acid-induced epilepsy in rats. J Ethnopharmacol 2007; 109: 241-7. https://doi.org/10.1016/j.jep.2006.07.024 ##Huang RQ, Bell-Horner CL, Dibas MI, Covey DF, Drewe JA, Dillon GH. Pentylenetetrazole-induced inhibition of recombinant gamma-aminobutyric acid type A (GABA(A)) receptors: mechanism and site of action. J Pharmacol Exp Ther 2001; 298: 986-95.##Inaloo S, Pirsalami F, Dastgheib M, Moezi L. The effects of dairy products on seizure tendency in mice. Heliyon 2019; 5: e01331. https://doi.org/10.1016/j.heliyon.2019.e01331 ##Jahan AA, Rad A, Ghanbarabadi M, Amin B, Mohammad-Zadeh M. The role of serotonin and its receptors on the anticonvulsant effect of curcumin in pentylenetetrazol-induced seizures. Life Sci 2018; 211: 252-60. https://doi.org/10.1016/j.lfs.2018.09.007##Jithan AV, Madhavi K, Madhavi M, Prabhakar K. Preparation and characterization of albumin nanoparticles encapsulating curcumin intended for the treatment of breast cancer. Int J Pharm Invest 2011; 1: 119-25. https://doi.org/10.4103/2230-973X.82432 ##Karimi M, Bahrami S, Ravari SB, Zangabad PS, Mirshekari H, Bozorgomid M, et al. Albumin nanostructures as advanced drug delivery systems. Expert Opin Drug Del 2016; 13: 1609-23.https://doi.org/10.1080/17425247.2016.1193149 ##Kaur H, Bal A, Sandhir R. Curcumin supplementation improves mitochondrial and behavioral deficits in experimental model of chronic epilepsy. Pharmacol Biochem Behav 2014; 125: 55-64.https://doi.org/10.1016/j.pbb.2014.08.001 ##Khadrawy YA, Sawie HG, Hosny EN. Neuroprotective effect of curcumin nanoparticles against rat model of status epilepticus induced by pilocarpine. J Complement Integr Med 2018; 15.https://doi.org/10.1515/jcim-2017-0117 ##Khan MS, Muhammad T. Dietary supplementation of the antioxidant curcumin halts systemic LPS-induced neuroinflammation-associated neurodegeneration and memory/synaptic impairment via the JNK/NF-κB/Akt signaling pathway in adult rats. Oxid Med Cell Longev 2019; 2019: 7860650.https://doi.org/10.1155/2019/7860650 ##Kiasalari Z, Roghani M, Khalili M, Rahmati B, Baluchnejadmojarad T. Antiepileptogenic effect of curcumin on kainate-induced model of temporal lobe epilepsy. Pharm Biol 2013; 51: 1572-8.https://doi.org/10.3109/13880209.2013.803128 ##Kim TH, Jiang HH, Youn YS, Park CW, Tak KK, Lee S, et al. Preparation and characterization of water-soluble albumin-bound curcumin nanoparticles with improved antitumor activity. Int J Pharm 2011; 403: 285-91. https://doi.org/10.1016/j.ijpharm.2010.10.041 ##Kobylarek D, Iwanowski P, Lewandowska Z, Limphaibool N, Szafranek S, Labrzycka A, et al. Advances in the potential biomarkers of epilepsy. Front Neurol 2019; 10. https://doi.org/10.3389/fneur.2019.00685 ##Kocaadam B, Sanlier N. Curcumin, an active component of turmeric (curcuma longa), and its effects on health. Crit Rev Food Sci Nutr 2017; 57: 2889-95. https://doi.org/10.1080/10408398.2015.1077195 ##Kratz F. Albumin as a drug carrier: Design of prodrugs, drug conjugates and nanoparticles. J Control Release 2008; 132: 171-83. https://doi.org/10.1016/j.jconrel.2008.05.010 ##Kumar V, Prakash C, Singh R, Sharma D. Curcumin’s antiepileptic effect, and alterations in nav1.1 and nav1.6 expression in iron-induced epilepsy. Epilepsy Res 2019; 150: 7-16.https://doi.org/10.1016/j.eplepsyres.2018.12.007 ##Kupferberg H. Animal models used in the screening of antiepileptic drugs. Epilepsia 2001; 42 Suppl 4: 7-12. https://doi.org/10.1046/j.1528-1157.2001.0420s4007.x ##Loscher W, Honack D, Fassbender CP, Nolting B. The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. III. Pentylenetetrazole seizure models. Epilepsy Res 1991; 8: 171-89. https://doi.org/10.1016/0920-1211(91)90062-K ##Loscher W, Lehmann H. L-deprenyl (selegiline) exerts anticonvulsant effects against different seizure types in mice. J Pharmacol Exp Ther 1996; 277: 1410-7. ##Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem 1951; 193: 265-75. ##Mandhane SN, Aavula K, Rajamannar T. Timed pentylenetetrazol infusion test: a comparative analysis with s.C.PTZ and MES models of anticonvulsant screening in mice. Seizure 2007; 16: 636-44.https://doi.org/10.1016/j.seizure.2007.05.005 ##Mielke K, Brecht S, Dorst A, Herdegen T. Activity and expression of JNK1, p38 and ERK kinases, c-Jun N-terminal phosphorylation, and c-jun promoter binding in the adult rat brain following kainate-induced seizures. Neuroscience 1999; 91: 471-83. https://doi.org/10.1016/S0306-4522(98)00667-8 ##Moezi L, Yahosseini S, Jamshidzadeh A, Dastgheib M, Pirsalami F. Sub-chronic boldine treatment exerts anticonvulsant effects in mice. Neurol Res 2018; 40: 146-52. https://doi.org/10.1080/01616412.2017.1402500 ##Moosavi M, Abbasi L, Zarifkar A, Rastegar K. The role of nitric oxide in spatial memory stages, hippocampal erk and camkii phosphorylation. Pharmacol Biochem Behav 2014; 122: 164-72. https://doi.org/10.1016/j.pbb.2014.03.021##Morgan L, Neame SJ, Child H, Chung R, Shah B, Barden L, et al. Development of a pentylenetetrazole-induced seizure model to evaluate kinase inhibitor efficacy in the central nervous system. Neurosci Lett 2006; 395: 143-8. https://doi.org/10.1016/j.neulet.2005.10.068 ##Nutt DJ, Taylor SC, Little HJ. Optimizing the pentetrazol infusion test for seizure threshold measurement. J Pharm Pharmacol 1986; 38: 697-8. https://doi.org/10.1111/j.2042-7158.1986.tb03114.x##Peng DU, Tang HY, Xin LI, Lin HJ, Peng WF, Yu MA, et al. Anticonvulsive and antioxidant effects of curcumin on pilocarpine-induced seizures in rats. Chin Med J (Engl) 2012; 125: 1975-9. ##Rein MJ, Renouf M, Cruz-Hernandez C, Actis-Goretta L, Thakkar SK, da Silva Pinto M. Bioavailability of bioactive food compounds: A challenging journey to bioefficacy. Br J Clin Pharmacol 2013; 75: 588-602.https://doi.org/10.1111/j.1365-2125.2012.04425.x ##Rogawski MA. Molecular targets versus models for new antiepileptic drug discovery. Epilepsy Res 2006; 68: 22-8. https://doi.org/10.1016/j.eplepsyres.2005.09.012 ##Saha L, Chakrabarti A, Kumari S, Bhatia A, Banerjee D. Antiapoptotic and neuroprotective role of Curcumin in Pentylenetetrazole (PTZ) induced kindling model in rat. Indian J Exp Biol 2016; 54: 133-41. ##Scheepens A, Tan K, Paxton JW. Improving the oral bioavailability of beneficial polyphenols through designed synergies. Genes Nutr 2010; 5: 75-87. https://doi.org/10.1007/s12263-009-0148-z ##Shafaroodi H, Moezi L, Ghorbani H, Zaeri M, Hassanpour S, Hassanipour M, et al. Sub-chronic treatment with pioglitazone exerts anti-convulsant effects in pentylenetetrazole-induced seizures of mice: the role of nitric oxide. Brain Res Bull 2012; 87: 544-50. https://doi.org/10.1016/j.brainresbull.2012.02.001 ##Shafaroodi H, Oveisi S, Hosseini M, Niknahad H, Moezi L. The effect of acute aripiprazole treatment on chemically and electrically induced seizures in mice: the role of nitric oxide. Epilepsy Behav 2015; 48: 35-40. https://doi.org/10.1016/j.yebeh.2015.05.018 ##Sookhaklari R, Geramizadeh B, Abkar M, Moosavi M. The neuroprotective effect of BSA-based nanocurcumin against 6-OHDA-induced cell death in SH-SY5Y cells. Basic Clin Neurosci 2019; 9: 92-100. ##SoukhakLari R, Moezi L. Curcumin-loaded bsa nanoparticles protect more efficiently than natural curcumin against scopolamine-induced memory retrieval deficit. Basic Clin Neurosci 2019; 10: 157-64. ##SoukhakLari R, Moezi L, Pirsalami F, Ashjazadeh N, Moosavi M. Curcumin ameliorates scopolamine-induced mice memory retrieval deficit and restores hippocampal p-Akt and p-GSK-3β. Eur J Pharmacol 2018a; 841: 28-32. https://doi.org/10.1016/j.ejphar.2018.10.012 ##SoukhakLari R, Moezi L, Pirsalami F, Ashjazadeh N, Moosavi M. The passive avoidance memory improving effect of curcumin in young adult mice: considering hippocampal MMP-2, MMP-9 and Akt/GSK3β. Pharma-Nutrition 2018b; 6: 95-9. https://doi.org/10.1016/j.phanu.2018.05.002 ##SoukhakLari R, Moezi L, Pirsalami F, Moosavi M. The effect of BSA-based curcumin nanoparticles on mem-ory and hippocampal MMP-2, MMP-9, and MAPKs in adult mice. J Mol Neurosci 2018c; 65: 319-26.https://doi.org/10.1007/s12031-018-1104-4 ##Spigolon G, Veronesi C, Bonny C, Vercelli A. c-Jun N-terminal kinase signaling pathway in excitotoxic cell death following kainic acid-induced status epilepticus. Eur J Neurosci 2010; 31: 1261-72.https://doi.org/10.1111/j.1460-9568.2010.07158.x ##Sumanont Y, Murakami Y, Tohda M, Vajragupta O, Watanabe H, Matsumoto K. Effects of manganese complexes of curcumin and diacetylcurcumin on kainic acid-induced neurotoxic responses in the rat hippocampus. Biol Pharm Bull 2007; 30: 1732-9. https://doi.org/10.1248/bpb.30.1732 ##Tai TY, Warner LN, Jones TD, Jung S, Concepcion FA, Skyrud DW, et al. Antiepileptic action of c-jun n-terminal kinase (jnk) inhibition in an animal model of temporal lobe epilepsy. Neuroscience 2017; 349: 35-47. https://doi.org/10.1016/j.neuroscience.2017.02.024 ##Tang F, Hartz AMS, Bauer B. Drug-resistant epilepsy: multiple hypotheses, few answers. Front Neurol 2017; 8: 301. https://doi.org/10.3389/fneur.2017.00301 ##Tønnesen HH. Solubility, chemical and photochemical stability of curcumin in surfactant solutions. Studies of curcumin and curcuminoids, XXVIII. Die Pharmazie 2002; 57: 820-4. ##Vidaurre J, Gedela S, Yarosz S. Antiepileptic drugs and liver disease. Pediatr Neurol 2017; 77: 23-36. https://doi.org/10.1016/j.pediatrneurol.2017.09.013 ##Wahlstrom B, Blennow G. A study on the fate of curcumin in the rat. Acta Pharmacol Toxicol (Copenh) 1978; 43: 86-92. https://doi.org/10.1111/j.1600-0773.1978.tb02240.x ##Wang Z, Chen Y, Lü Y, Chen X, Cheng L, Mi X, et al. Effects of JIP3 on epileptic seizures: evidence from temporal lobe epilepsy patients, kainic-induced acute seizures and pentylenetetrazole-induced kindled seizures. Neuroscience 2015; 300: 314-24. https://doi.org/10.1016/j.neuroscience.2015.05.008 ##Yang DD, Kuan CY, Whitmarsh AJ, Rinócn M, Zheng TS, Davis RJ, et al. Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the jnk3 gene. Nature 1997; 389: 865-70. https://doi.org/10.1038/39899 ##Yarza R, Vela S, Solas M, Ramirez MJ. c-Jun N-terminal kinase (JNK) signaling as a therapeutic target for Alzheimer’s disease. Front Pharmacol 2016; 6: 321. https://doi.org/10.3389/fphar.2015.00321 ##Zhang W, Wang X, Yu M, Li JA, Meng H. The c-Jun N-terminal kinase signaling pathway in epilepsy: activation, regulation, and therapeutics. J Recept Signal Transduct 2018; 38: 492-8. https://doi.org/10.1080/10799893.2019.1590410 ##Zhao W, Zhou X, Qi G, Guo Y. Curcumin suppressed the prostate cancer by inhibiting jnk pathways via epigenetic regulation. J Biochem Mol Toxicol 2018; 32: e22049. https://doi.org/10.1002/jbt.22049 ##Zhao Y, Spigolon G, Bonny C, Culman J, Vercelli A, Herdegen T. The jnk inhibitor d-jnki-1 blocks apoptotic jnk signaling in brain mitochondria. Mol Cell Neurosci 2012; 49: 300-10. https://doi.org/10.1016/j.mcn.2011.12.005## ##

Comparison of the protective effects of Scrophularia striata extract with vitamin E on cognitive function, anxiety and pain sensitivity in diazinon-exposed male rats 2 2 Introduction: Scrophularia striata is used in traditional medicine to treat various disorders and has neuroprotective effects. There are no studies about the effects of S. striata on cognitive functions in diazinon (DZN)- exposed rats. According to the results of previous studies, vitamin E (Vit. E) can also act as a protective agent against cognitive impairments. Therefore, the present study was designed to compare the effects of Vit. E and S. striata on DZN-induced behavioral impairments in male rats. Methods: Neuroprotective effects of S. striata (30mg/kg, 5 days/week for 8 weeks) and Vit. E (200mg/kg, 5 days/week for 8 weeks, IP) were assessed through changes in memory, anxiety-like behaviors and pain threshold following DZN exposure. Open field, shuttle box and hot plate were used to examine anxiety-like behaviors, passive avoidance learning and memory as well as pain sensitivity, respectively. Results: Our findings indicated that exposure to DZN caused a significant decrease in memory retention and an increase in anxiety-like behaviors. S. striata and Vit. E administration compensated memory and emotional impairments induced by DZN. As well as, S. striata alone decreased reaction time against thermal stimulus in the hot plate test. The findings of the present study also indicated that exposure to DZN significantly decreased body weight, while S. striata and Vit. E consumption restored it. Conclusion: Results of our study indicated the protective effects of S. striata consumption like Vit. E against DZN-induced disruptions in anxiety, cognitive function and body weight loss. 47 56 2020/04/242020/06/152020/07/222020/07/82020/02/8 1398/11/19 2020/07/252020/12/12020/10/272020/10/272020/08/15 1399/5/25 Ali Abedi Ali Abedi Department of Physiology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran Iran A.abedi@arums.ac.ir Khayam Bamdad Khayam Bamdad School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran Iran Kh.bamdad@arums.ac.ir Hilda Yaghoubi Shahir Hilda Yaghoubi Shahir School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran Iran H.yaghoubishahir@arums.ac.ir Raziyeh Dehghany Raziyeh Dehghany School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran Iran Raziyeh.dehgani@arums.ac.ir Alireza Moradi Alireza Moradi School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran Iran Hakimeh Saadati Hakimeh Saadati Department of Physiology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran Iran h.saadati@arums.ac.ir Vitamin E Scrophularia striata Diazinon Cognitive functions Anxiety-like behaviors Nociception. Abdel-Diam MM, Samak DH, El-Sayed YS, Aleya L, Alarifi S, Alkahtani S. Curcumin and quercetin synergistically attenuate subacute diazinon-induced inflammation and oxidative neurohepatic damage, and acetylcholinesterase inhibition in albino rats. Environ Sci Pollut Res 2019; 26: 3659-65. https://doi.org/10.1007/s11356-018-3907-9 ##AL-Shinnawy MS. Effects of orally fed diazinon on some biochemical parameters of male albino rats. Egypt J Hosp Med 2008; 33: 559-68.##Alqasoumi SI. Evaluation of the hepatroprotective and nephroprotective activities of Scrophularia hypericifolia growing in Saudi Arabia. Saudi Pharm J 2014; 22: 258-63. https://doi.org/10.1016/j.jsps.2013.12.001##Altuntas I, Kilinc I, Orhan H, Demirel R, Koylu H, Delibas N. The effects of diazinon on lipid peroxidation and antioxidant enzymes in erythrocytes in vitro. Hum Exp Toxicol 2004; 23: 9-13. https://doi.org/10.1191/0960327104ht408oa##Androutsopoulos VP, Kanavouras K, Tsatsakis AM. Role of paraoxonase 1 (PON1) in organophosphate metabolism: implications in neurodegenerative diseases. Toxicol Appl Pharmacol 2011; 256: 418-24. https://doi.org/10.1016/j.taap.2011.08.009##Ardeshiri-Lagimi A, Barzegar MA, Rezaei-Tavirani M, Hashemi ME, Heidari-Kashal S, Moghaddamnia SH, et al. Effects of Scrophularia striata extract on human fibroblast cells. Med Sci J Islamic Azad Univ 2009; 19.##Azadmehr A, Hajiaghaee R, Afshari A, Amirghofran Z, Refieian-Kopaei M, Yousofi Darani H, et al. Evaluation of in vivo immune response activity and in vitro anti-cancer effect by Scrophularia megalantha. J Med Plant Res 2011; 5: 2365-8.##Azadmehr A, Maliji G, Hajiaghaee R, Shahnazi M, Afaghi A. Inhibition of pro-inflammatory cytokines by ethyl acetate extract of Scrophularia striata. trop j pharm res 2012; 11: 893-7. https://doi.org/10.4314/tjpr.v11i6.4##Azadmehr A, Oghyanous KA, Hajiaghaee R, Amirghofran Z, Azadbakht M. Antioxidant and neuroprotective effects of scrophularia striata extract against oxidative stress-induced neurotoxicity. Cell Mol Neurobiol 2013; 33: 1135-41. https://doi.org/10.1007/s10571-013-9979-7##Babri S, Doosti MH, Fatehi L, Salari AA. The effects of Scrophularia striata extract on anxiety and depression behaviors in adult male mice. Pharm Sci 2012; 18: 133-40.##Bali YA, Kaikai NE, Ba-M’hamed S, Bennis M. Learning and memory impairments associated to acetylcholinesterase inhibition and oxidative stress following glyphosate based-herbicide exposure in mice. Toxicology 2019; 415: 18-25. https://doi.org/10.1016/j.tox.2019.01.010##Chen Y. Organophosphate-induced brain damage: mechanisms, neuropsychiatric and neurological consequences, and potential therapeutic strategies. Neurotoxicology 2012; 33: 391-400. https://doi.org/10.1016/j.neuro.2012.03.011##de Santos Galíndez J, Díaz Lanza A, Fernandez Matellano L. Biologically active substances from the genus Scrophularia. Pharm Biol 2002; 40: 45-59. https://doi.org/10.1076/phbi.40.1.45.5864##Diaz AM, Abad MJ, Fernandez L, Silvan AM, De Santos J, Bermejo P. Phenylpropanoid glycosides from Scrophularia scorodonia: in vitro anti-inflammatory activity. Life Sci 2004; 74: 2515-26. https://doi.org/10.1016/j.lfs.2003.10.008##El-Shenawy NS, El-Salmy F, Al-Eisa RA, El-Ahmary B. Amelioratory effect of vitamin E on organophosphorus insecticide diazinon-induced oxidative stress in mice liver. Pestic Biochem Phys 2010; 96: 101-7. https://doi.org/10.1016/j.pestbp.2009.09.008##Fukui K, Omoi NO, Hayasaka T, Shinnkai T, Suzuki S, Abe K, et al. Cognitive impairment of rats caused by oxidative stress and aging, and its prevention by vitamin E. Ann N Y Acad Sci 2002; 959: 275-84. https://doi.org/10.1111/j.1749-6632.2002.tb02099.x##Hasanein P, Shahidi S. Effects of combined treatment with vitamins C and E on passive avoidance learning and memory in diabetic rats. Neurobiol Learn Mem 2010; 93: 472-8. https://doi.org/10.1016/j.nlm.2010.01.004##Huen K, Bradman A, Harley K, Yousefi P, Boyd Barr DB, Eskenazi B, et al. Organophosphate pesticide levels in blood and urine of women and newborns living in an agricultural community. Environ Res 2012; 117: 8-16. https://doi.org/10.1016/j.envres.2012.05.005##Kim SR, Kang SY, Lee KY, Kim SH, Markelonis GJ, Oh TH, et al. Anti-amnestic activity of E-p-methoxycinnamic acid from Scrophularia buergeriana. Brain Res Cogn Brain Res 2003; 17: 454-61. https://doi.org/10.1016/S0926-6410(03)00161-7##Kim SR, Kim YC. Neuroprotective phenylpropanoid esters of rhamnose isolated from roots of Scrophularia buergeriana. Phytochemistry 2000; 54: 503-9. https://doi.org/10.1016/S0031-9422(00)00110-2##Kim SR, Lee KY, Koo KA, Sung SH, Lee NG, Kim J, et al. Four new neuroprotective iridoid glycosides from Scrophularia b uergeriana roots. J Nat Prod 2002; 65: 1696-9. https://doi.org/10.1021/np0202172##López-Crespo G, Flores P, Sánchez-Santed F, Sánchez-Amate M. Acute high dose of chlorpyrifos alters performance of rats in the elevated plus-maze and the elevated T-maze. Neurotoxicology 2009; 30: 1025-9. https://doi.org/10.1016/j.neuro.2009.07.009##Mamiya T, Kise M, Morikawa K. Ferulic acid attenuated cognitive deficits and increase in carbonyl proteins induced by buthionine-sulfoximine in mice. Neurosci Lett 2008; 430: 115-8. https://doi.org/10.1016/j.neulet.2007.10.029##Maxwell DM, Brecht KM, Koplovitz I, Sweeney RE. Acetylcholinesterase inhibition: does it explain the toxicity of organophosphorus compounds? Arch Toxicol 2006; 80: 756. https://doi.org/10.1007/s00204-006-0120-2##Naseh M, Vatanparast J, Baniasadi M, Hamidi GA. Alterations in nitric oxide synthase-expressing neurons in the forebrain regions of rats after developmental exposure to organophosphates. Neurotoxicol Teratol 2013; 37: 23-32. https://doi.org/10.1016/j.ntt.2013.02.003##Nili-Ahmadabadi A, Ali-Heidar F, Ranjbar A, Mousavi L, Ahmadimoghaddam D, Larki-Harchegani A, et al. Protective effect of amlodipine on diazinon-induced changes on oxidative/antioxidant balance in rat hippocampus. Res Pharm Sci 2018; 13: 368-76. https://doi.org/10.4103/1735-5362.235164##Poirier L, Jacquet P, Plener L, Masson P, Daudé D, Chabrière E. Organophosphorus poisoning in animals and enzymatic antidotes. Environ Sci Pollut Res 2018; 29: 1-26. https://doi.org/10.1007/s11356-018-2465-5##Rush T, Liu XQ, Hjelmhaug J, Lobner D. Mechanisms of chlorpyrifos and diazinon induced neurotoxicity in cortical culture. Neuroscience 2010; 166: 899-906. https://doi.org/10.1016/j.neuroscience.2010.01.025##Saadati H, Babri S, Ahmadiasl N, Mashhadi M. Effects of exercise on memory consolidation and retrieval of passive avoidance learning in young male rats. Asian J Sports Med 2010; 1: 137. https://doi.org/10.5812/asjsm.34858##Saadati H, Sheibani V. Effects of exercise and/or sleep deprivation on anxiety-Like behavior and body weight of female rats. Asian J Psychiatr 2017; 28: 26-7. https://doi.org/10.1016/j.ajp.2017.02.028##Sadegzadeh F, Sakhaie N, Isazadehfar K, Saadati H. Effects of exposure to enriched environment during adolescence on passive avoidance memory, nociception, and prefrontal BDNF level in adult male and female rats. Neurosci Lett 2020; 732: 135133. https://doi.org/10.1016/j.neulet.2020.135133##Sakhaie N, Sadegzadeh F, Dehghany R, Adak O, Hakimeh S. Sex-dependent effects of chronic fluoxetine exposure during adolescence on passive avoidance memory, nociception, and prefrontal brain-derived neurotrophic factor mRNA expression. Brain Res Bull 2020a; 162: 231-6. https://doi.org/10.1016/j.brainresbull.2020.06.009##Sakhaie N, Sadegzadeh F, Mohammadnia A, Dadkhah M, Saadati H. Sex-dependent effects of post-weaning exposure to an enriched environment on novel objective recognition memory and anxiety-like behaviors: the role of hippocampal BDNF level. Int J Dev Neurosci 2020b. https://doi.org/10.1002/jdn.10038##Salavati P, Ramezani M, Monsef-Esfahani HR, Hajiagha R, Parsa M, Tavajohi S, et al. Neuroprotective effect of total and sequential extract of Scrophularia striata Boiss. in rat cerebellar granule neurons following glutamate-induced neurotoxicity: an in-vitro study. Iran J Pharm Res 2013; 12: 389.##Sapbamrer R, Hongsibsong S. Effects of prenatal and postnatal exposure to organophosphate pesticides on child neurodevelopment in different age groups: a systematic review. Environ Sci Pollut Res 2019; 26: 18267-90. https://doi.org/10.1007/s11356-019-05126-w##Shokrzadeh M, Payam SS, Zargari M, Abasi A, Abedian S, Layali I, et al. The protective effect of vitamin A, C, and E on the superoxide dismutase enzyme activity in rat erythrocytes exposed to diazinon. J Mazandaran Univ Med Sci 2012; 21: 30-8.##Slotkin TA, Seidler FJ, Fumagalli F. Targeting of neurotrophic factors, their receptors, and signaling pathways in the developmental neurotoxicity of organophosphates in vivo and in vitro. Brain Res Bull 2008; 76: 424-38. https://doi.org/10.1016/j.brainresbull.2008.01.001##Sofiabadi M, Azadmehr A, Hajiaghaei R, Rezazadeh S, Ajdari Zarmehri H. The effect of ethanolic extract of scrophularia striata on pain in male rats. J Med Plant Res 2012; 2: 113-9.##Takatsu H, Owada K, Abe K, Nakano M, Urano S. Effect of vitamin E on learning and memory deficit in aged rats. J Nutr Sci Vitaminol 2009; 55: 389-93. https://doi.org/10.3177/jnsv.55.389##Timofeeva OA, Roegge CS, Seidler FJ, Slotkin TA, Levin ED. Persistent cognitive alterations in rats after early postnatal exposure to low doses of the organophosphate pesticide, diazinon. Neurotoxicol Teratol 2008; 30: 38-45. https://doi.org/10.1016/j.ntt.2007.10.002##Win-Shwe TT, Nakajima D, Ahmed S, Fujimaki H. Impairment of novel object recognition in adulthood after neonatal exposure to diazinon. Arch Toxicol 2013; 87: 753-62. https://doi.org/10.1007/s00204-012-0989-x##Wu A, Ying Z, Gomez-Pinilla F. Vitamin E protects against oxidative damage and learning disability after mild traumatic brain injury in rats. Neurorehabil Neural Repair 2010; 24: 290-8. https://doi.org/10.1177/1545968309348318##Yu F, Wang Z, Ju B, Wang Y, Wang J, Bai D. Apoptotic effect of organophosphorus insecticide chlorpyrifos on mouse retina in vivo via oxidative stress and protection of combination of vitamins C and E. Exp Toxicol Pathol 2008; 59: 415-23. https://doi.org/10.1016/j.etp.2007.11.007##Zengin G, Stefanucci A, Rodrigues MJ, Mollica A, Custodio L, Aumeeruddy MZ, et al. Scrophularia lucida L. as a valuable source of bioactive compounds for pharmaceutical applications: In vitro antioxidant, anti-inflammatory, enzyme inhibitory properties, in silico studies, and HPLC profiles. J Pharm Biomed Anal 2019; 162: 225-33. https://doi.org/10.1016/j.jpba.2018.09.035## ##

The blockade of D1/D2-like dopamine receptors in the lateral periaqueductal gray region affects morphine self-administration with and without exercise in rats 2 2 Introduction: The periaqueductal gray (PAG) region plays an essential role in the modulation of nociception. Also, lateral PAG (lPAG) is involved in reward circuitry by the dopaminergic system in addiction. The present study investigated the blockade of D1/D2-like dopamine receptors in the lateral PAG region affects morphine self-administration with and without exercise. Methods: Rats were divided into six groups. The rats were initially trained to receive small pellets of food by pressing an active lever in the self administration apparatus. Exercise groups were run on a treadmill at 20m/min, 5 days/week, for 4 weeks before the surgery. Then rats were bilaterally implanted with cannulae in lPAG. The SCH23390 and sulpiride were microinjected into the lPAG, 5min before receiving morphine. Afterward, the animals were allowed to self administer morphine in 2h sessions over 11 consecutive days. At last, the numbers of lever pressing, infusion times and withdrawal symptoms were measured. Results: The results showed the number of active lever pressing was significantly increased in the morphine group compared to other groups in self-infusion during 11 days. Exercise significantly reversed the detrimental effects of morphine self-administration after five days. However, the synergistic effect of injected sulpiride into the lPAG region with exercise training was more pronounced on the amelioration of morphine than on the combinatory effect of SCH23390 with exercise. Conclusion: The findings suggested that the D2 dopamine receptor in the lPAG region was involved in the morphine addiction via the dopaminergic system and exercise training in combination with antagonists could reduce the rewarding properties of morphine. 57 68 2020/04/242020/06/152020/07/222020/07/82020/02/82019/08/25 1398/6/3 2020/07/252020/12/12020/10/272020/10/272020/08/152020/10/18 1399/7/27 Somayeh Ahmadi Somayeh Ahmadi Department of Physiology, Faculty of Physical Education and Sports Science, University of Isfahan, Isfahan, Iran Iran sap.ahmadi69@gmail.com Maryam Radahmadi Maryam Radahmadi Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Iran m_radahmadi@med.mui.ac.ir Safoura Alizadeh Safoura Alizadeh Department of Physiology, Faculty of Physical Education and Sports Science, University of Isfahan, Isfahan, Iran Iran Hojjatallah Alaei Hojjatallah Alaei Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Iran alaei@med.mui.ac.ir Mehdi Kargarfard Mehdi Kargarfard Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Iran kargar_m46@yahoo.com Effat Ramshini Effat Ramshini Department of Physiology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran Iran Periaqueductal gray Self-administration Exercise Morphine. Ahmadi S, Radahmadi M, Alaei H, Ramshini E. Effect of aerobic exercise on morphine self administration and pain modulation in rats. Adv Biomed Res 2018; 7: 70-81. https://doi.org/10.4103/abr.abr_181_17 ##Alaei H, Esmaeili M, Nasimi A, Pourshanazari A. Ascorbic acid decreases morphine self-administration and withdrawal symptoms in rats. Pathophysiology 2005; 12: 103-7. https://doi.org/10.1016/j.pathophys.2005.03.004 ##Avila-Luna A, Prieto-Leyva J, Galvez-Rosas A, Alfaro-Rodriguez A, Gonzalez-Pina R, Bueno-Nava A. D1 antagonists and d2 agonists have opposite effects on the metabolism of dopamine in the rat striatum. Neurochem Res 2015; 40: 1431-7. https://doi.org/10.1007/s11064-015-1611-4 ##Boecker H, Sprenger T, Spilker ME, Henriksen G, Koppenhoefer M, Wagner KJ, et al. The runner’s high: opioidergic mechanisms in the human brain. Cereb Cortex 2008; 18: 2523-31. https://doi.org/10.1093/cercor/bhn013 ##Charmchi E, Zendehdel M, Haghparast A. The effect of forced swim stress on morphine sensitization: Involvement of d1/d2-like dopamine receptors within the nucleus accumbens. Prog Neuropsychopharmacol Biol Psychiatry 2016; 70: 92-9. https://doi.org/10.1016/j.pnpbp.2016.05.006 ##Flores JA, El Banoua F, Galan-Rodriguez B, Fernandez-Espejo E. Opiate anti-nociception is attenuated following lesion of large dopamine neurons of the periaqueductal grey: Critical role for D1 (not D2) dopamine receptors. Pain 2004; 110: 205-14. https://doi.org/10.1016/j.pain.2004.03.036 ##Greenwood BN, Fleshner M. Exercise, stress resistance, and central serotonergic systems. Exerc Sport Sci Rev 2011; 39: 140-49. https://doi.org/10.1097/JES.0b013e31821f7e45 ##Haghparast A, Omranifard A, Arezoomandan R, Ghalandari-Shamami M, Taslimi Z, Vafaei AA, et al. Involvement of dopaminergic receptors of the rat nucleus accumbens in decreasing the conditioned place preference induced by lateral hypothalamus stimulation. Neurosci Lett 2013; 556: 10-4. https://doi.org/10.1016/j.neulet.2013.09.062 ##Hasue RH, Shammah-Lagnado SJ. Origin of the dopaminergic innervation of the central extended amygdala and accumbens shell: a combined retrograde tracing and immunohistochemical study in the rat. J Comp Neurol 2002; 454: 15-33. https://doi.org/10.1002/cne.10420 ##Hosseini M, Alaei HA, Havakhah S, Neemati Karimooy HA, Gholamnezhad Z. Effects of microinjection of angiotensin ii and captopril to vta on morphine self-administration in rats. Acta Biol Hung 2009a; 60: 241-52. ##Hosseini M, Alaei HA, Naderi A, Sharifi MR, Zahed R. Treadmill exercise reduces self-administration of morphine in male rats. Pathophysiology 2009b; 16: 3-7. https://doi.org/10.1016/j.pathophys.2008.11.001 ##Hoveida R, Alaei H, Oryan S, Parivar K, Reisi P. Treadmill running improves spatial memory in an animal model of alzheimer’s disease. Behav Brain Res 2011; 216: 270-4. https://doi.org/10.1016/j.bbr.2010.08.003 ##Hyman SE, Malenka RC, Nestler EJ. Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 2006; 29: 565-98. https://doi.org/10.1146/annurev.neuro.29.051605.113009 ##Lane DA, Patel PA, Morgan MM. Evidence for an intrinsic mechanism of antinociceptive tolerance within the ventrolateral periaqueductal gray of rats. Neuroscience 2005; 135: 227-34. https://doi.org/10.1016/j.neuroscience.2005.06.014 ##Li C, Sugam JA, Lowery-Gionta EG, McElligott ZA, McCall NM, Lopez AJ, et al. Mu opioid receptor modulation of dopamine neurons in the periaqueductal gray/dorsal raphe: a role in regulation of pain. Neuropsychopharmacology 2016; 41: 2122-32. https://doi.org/10.1038/npp.2016.12 ##Liu J, Chen L, Chen X, Hu K, Tu Y, Lin M, et al. Modulatory effects of different exercise modalities on the functional connectivity of the periaqueductal grey and ventral tegmental area in patients with knee osteoarthritis: A randomised multimodal magnetic resonance imaging study. Br J Anaesth 2019; 123: 506-18. https://doi.org/10.1016/j.bja.2019.06.017 ##Liu Y, Wu YW, Qian ZQ, Yan CF, Fan KM, Xu JH, et al. Effect of opioid receptors on acute stress-induced changes in recognition memory. Sheng Li Xue Bao 2016; 68: 757-66. ##Łupina M, Tarnowski M, Baranowska-Bosiacka I, Talarek S, Listos P, Kotlińska J, et al. SB-334867 (an orexin-1 receptor antagonist) effects on morphine-induced sensitization in mice-a view on receptor mechanisms. Mol Neurobiol 2018; 55: 8473-85. https://doi.org/10.1007/s12035-018-0993-0 ##Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA. Exercise as a novel treatment for drug addiction: A neurobiological and stage-dependent hypothesis. Neurosci Biobehav Rev 2013; 37: 1622-44. https://doi.org/10.1016/j.neubiorev.2013.06.011 ##McDougall SA, Reichel CM, Cyr MC, Karper PE, Nazarian A, Crawford CA. Importance of D 1 receptors for associative components of amphetamine-induced behavioral sensitization and conditioned activity: a study using D 1 receptor knockout mice. Psychopharmacology 2005; 183: 20-30. https://doi.org/10.1007/s00213-005-0146-9 ##Meyer PJ, Fossum EN, Ingram SL, Morgan MM. Analgesic tolerance to microinjection of the μ-opioid agonist damgo into the ventrolateral periaqueductal gray. Neuropharmacology 2007; 52: 1580-5. https://doi.org/10.1016/j.neuropharm.2007.03.002 ##Meyer PJ, Morgan MM, Kozell LB, Ingram SL. Contribution of dopamine receptors to periaqueductal gray-mediated antinociception. Psychopharmacology 2009; 204: 531-40. https://doi.org/10.1007/s00213-009-1482-y ##Moradi M, Fatahi Z, Haghparast A. Blockade of D1-like dopamine receptors within the ventral tegmental area and nucleus accumbens attenuates antinociceptive responses induced by chemical stimulation of the lateral hypothalamus. Neurosci Lett 2015; 599: 61-66. https://doi.org/10.1016/j.neulet.2015.05.047 ##Nestler EJ. Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2001; 2: 119-28. https://doi.org/10.1038/35053570 ##Paxinos G, Watson C. The rat brain in stereotaxic coordinates. London: Elsevier Academic, 2006. ##Reisi Z, Bani-Ardalan M, Zarepour L, Haghparast A. Involvement of D1/D2 dopamine receptors within the nucleus accumbens and ventral tegmental area in the development of sensitization to antinociceptive effect of morphine. Pharmacol Biochem Behav 2014; 118: 16-21. https://doi.org/10.1016/j.pbb.2013.12.023 ##Robison LS, Swenson S, Hamilton J, Thanos PK. Exercise reduces dopamine D1R and increases D2R in rats: implications for addiction. Med Sci Sports Exerc 2018; 50: 1596-602. https://doi.org/10.1249/MSS.0000000000001627 ##Sadeghzadeh F, Babapour V, Haghparast A. Role of dopamine D1-like receptor within the nucleus accumbens in acute food deprivation-and drug priming-induced reinstatement of morphine seeking in rats. Behav Brain Res 2015; 287: 172-81. https://doi.org/10.1016/j.bbr.2015.03.055 ##Sahraei H, Poorheidari G, Foadaddini M, Khoshbaten A, Asgari A, Noroozzadeh A, et al. Effects of nitric oxide on morphine self-administration in rat. Pharmacol Biochem Behav 2004; 77: 111-6. https://doi.org/10.1016/j.pbb.2003.10.008 ##Schetz JA, Sibley DR. Dopaminergic neurotransmission. Handbook of contemporary neuropharmacology 2007. https://doi.org/10.1002/9780470101001.hcn007 ##Silva MT, Heyman GM. Chronic morphine consumption decreases wheel running and wheel running-reinforced behavior in rats. Pharmacol Biochem Behav 2001; 69: 51-7. https://doi.org/10.1016/S0091-3057(01)00498-1 ##Smith MA, Fronk GE, Abel JM, Lacy RT, Bills SE, Lynch WJ. Resistance exercise decreases heroin self-administration and alters gene expression in the nucleus accumbens of heroin-exposed rats. Psychopharmacology 2018; 235: 1245-55. https://doi.org/10.1007/s00213-018-4840-9 ##Smith MA, Lynch WJ. Exercise as a potential treatment for drug abuse: evidence from preclinical studies. Front Psychiatry 2011; 2: 82. https://doi.org/10.3389/fpsyt.2011.00082 ##Tobaldini G, Reis RA, Sardi NF, Lazzarim MK, Tomim DH, Lima M, et al. Dopaminergic mechanisms in periaqueductal gray-mediated antinociception. Behav Pharmacol 2018; 29: 225-33. https://doi.org/10.1097/FBP.0000000000000346 ##Volkow ND, Baler RD. Addiction science: Uncovering neurobiological complexity. Neuropharmacology 2014; 76: 235-49. https://doi.org/10.1016/j.neuropharm.2013.05.007 ##Voulalas PJ, Ji Y, Jiang L, Asgar J, Ro JY, Masri R. Loss of dopamine D1 receptors and diminished D1/5 receptor-mediated ERK phosphorylation in the periaqueductal gray after spinal cord lesion. Neuroscience 2017; 343: 94-105. https://doi.org/10.1016/j.neuroscience.2016.11.040 ##Yoshida K, Nonaka T, Nakamura S, Araki M, Yamamoto T. Microinjection of 26RFa, an endogenous ligand for the glutamine RF-amide peptide receptor (QRFP receptor), into the rostral ventromedial medulla (RVM), locus coelureus (LC), and periaqueductal grey (PAG) produces an analgesic effect in rats. Peptides 2019; 115: 1-7. https://doi.org/10.1016/j.peptides.2019.02.003## ##

Pretreatment with p-coumaric acid protect rat’s liver against ischemia-reperfusion injury 2 2 Introduction: Many physiological, biochemical and toxicological reactions are occurred in liver. Therefore, healthy function of this organ is vital for the whole body. In spite of having potent endogenous antioxidant system, lots of reactions in liver make it more susceptible to stressors. It is established that improving the potency of liver antioxidants can increase its ability to resist against different kinds of oxidative stressors. Therefore, this study designed to determine whether p-coumaric alleviate ischemia-reperfusion-induced hepatic injury (IRI) in rats. Methods: Thirty-two rats were randomly assigned in sham, p-coumaric acid (PC), ischemia-reperfusion (IR) and p-coumaric acid pretreated IR (PC+IR) groups (n=8 in each group). Animals in sham group underwent laparotomy but not IR injury; rats in PC group did not experience any surgical procedures; IR and PC+IR groups underwent hepatic IR injury. P-coumaric acid at 100mg/kg were given for 7 consecutive days to PC and PC+IR groups. The last dose of p-coumaric acid was injected just before surgery on 7th days of experiment. The levels of malondialdehyde, TAC, ALT and AST were determined. A molecular evaluation to quantify the gene expression of SOD and GPx was done in liver homogenate. Results: P-coumaric mitigated the hepatic injuries induced by IR and improved TAC, ALT, AST, SOD and GPx. This pretreatment was also decreased MDA level. Conclusion: The current outcomes showed that PC via improving the endogenous level of antioxidants in liver tissues and inhibiting IR-induced inflammation maintain the liver structure and function of liver against IR. 69 75 2020/04/242020/06/152020/07/222020/07/82020/02/82019/08/252020/03/11 1398/12/21 2020/07/252020/12/12020/10/272020/10/272020/08/152020/10/182020/08/4 1399/5/14 Razieh Kazemzadeh Razieh Kazemzadeh Persian Gulf’s Physiology Research Center, Medical Basic Sciences Research Institute , Alimentary Tract Research Center, Clinical Sciences Research Institute, Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran Iran KAZEMZADEHRAZIEH@gmail.com Layasadat Khorsandi Layasadat Khorsandi Cellular and Molecular Research Center, Department of Anatomical Sciences, Medical Basic Sciences Research Institute , School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Iran Iran khorsandi-l@ajums.ac.ir Maryam Radan Maryam Radan Persian Gulf’s Physiology Research Center, Medical Basic Sciences Research Institute , Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran Iran Radan.m@ajums.ac.ir Samireh Ghafouri Samireh Ghafouri Persian Gulf’s Physiology Research Center, Medical Basic Sciences Research Institute , Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran Iran Ghafouri-s@ajums.ac.ir Seyyed Ali Mard Seyyed Ali Mard Persian Gulf’s Physiology Research Center, Medical Basic Sciences Research Institute , Alimentary Tract Research Center, Clinical Sciences Research Institute, Department of Physiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran Iran mard-sa@ajums.ac.ir p-coumaric acid GPX SOD TAC Rat. Akbari G, Mard SA, Dianat M, Mansouri E. The hepatopro‌tective and MicroRNAs downregulatory effects of cro‌cin following hepatic ischemia-reperfusion injury in rats. Oxid Med Cell Longev 2017; 2017: 1702967. https://doi.org/10.1155/2017/1702967##Altay N, Karahan MA, Büyükfırat E, Yeşilay A, Yüce HH, Aydoğan H, et al. A combination of dexmedetomidine and thymoquinone is better able to prevent ischemia reperfu‌sion injuries in the liver: an experimental study in rat mod‌el. Int J Clin Exp Med 2016; 9: 2521-2527.##Carson P, Hong CJ, Otero-Vinas M, Arsenault EF, Falan‌ga V. Liver enzymes and lipid levels in patients with li-podermatosclerosis and venous ulcers treated with a prototypic anabolic steroid (stanozolol) a prospective, randomized, double-blinded, placebo-controlled trial. Int J Low Extrem Wounds 2015; 14: 11-8. https://doi.org/10.1177/1534734614562276##Cerqueira NF, Hussni CA, Yoshida WB. Pathophysiology of mesenteric ischemia/reperfusion: a review. Acta Ciru‌rgica Brasileira 2005; 20: 336-43. https://doi.org/10.1590/S0102-86502005000400013##Ekinci Akdemir FN, Albayrak M, Çalik M, Bayir Y, Gülçin. The protective effects of p-coumaric acid on acute liver and kidney damages induced by cisplatin. Biomedicines 2017; 5: 18. https://doi.org/10.3390/biomedicines5020018##Faqi AS, editor. Biomarkers in nonclinical drug development. In: A comprehensive guide to toxicology in nonclinical drug development. 2nd Edition. Boston: Academic Press, 2016.##Kadono K, Uchida Y, Hirao H, Miyauchi T, Watanabe T, Iida T, et al. Thrombomodulin attenuates inflammatory damage due to liver ischemia and reperfusion injury in mice in toll-like receptor 4-dependent manner. Am J Transplant 2017; 17: 69-80. https://doi.org/10.1111/ajt.13991##Kiris I, Okutan H, Savas C, Yonden Z, Delibas N. Gadolinium chloride attenuates aortic occlusion-reperfusion-induced myocardial injury in rats. Saudi Med J 2007; 28: 347.##Klune JR, Tsung A. Molecular biology of liver ischemia/reperfusion injury: established mechanisms and recent ad‌vancements. Surg Clin North Am 2010; 90: 665-77. https://doi.org/10.1016/j.suc.2010.04.003##Li S, Fujino M, Takahara T, Li XK. Protective role of heme oxygenase-1 in fatty liver ischemia-reperfusion injury. Med Mol Morphol 2019; 52: 61-72. https://doi.org/10.1007/s00795-018-0205-z##Mard SA, Pipelzadeh MH, Teimoori A, Neisi N, Mojahedin S, Khani MZ, et al. Protective activity of crocin against indo‌methacin-induced gastric lesions in rats. J Nat Med 2016; 70: 62-74. https://doi.org/10.1007/s11418-015-0938-0##Mitani T, Mimura H, Ikeda K, Nishide M, Yamaguchi M, Koyama H, et al. Process for the purification of cis-p-cou‌maric acid by cellulose column chromatography after the treatment of the trans isomer with ultraviolet irradiation. Anal Sci 2018; 34: 1195-9. https://doi.org/10.2116/anals‌ci.18P102##Nilsson U, Lundgren O, Haglind E, Bylund-Fellenius A. Radical production during in vivo intestinal ischemia and reperfusion in the cat. Am J Physiol Gastrointest 1989; 257: G409-14. https://doi.org/10.1152/ajpgi.1989.257.3.G409##Paller MS, Hoidal J, Ferris TF. Oxygen free radicals in isch‌emic acute renal failure in the rat. J Clin Investig 1984; 74: 1156-64. https://doi.org/10.1172/JCIcvv111524##Popova J, Buravkova L. Blood biochemical parameters in women during long-term simulated hyperoxic diving up to 8 ATA. Undersea Hyperb Med 2006; 33: 211-6.##Sakamula R, Thong-asa W. Neuroprotective effect of p-cou‌maric acid in mice with cerebral ischemia reperfusion injuries. Metab Brain Dis 2018; 33: 765-73. https://doi.org/10.1007/s11011-018-0185-7##Schoenberg MH, Fredholm BB, Haglund U, Jung H, Sellin D, Younes M, et al. Studies on the oxygen radical mech‌anism involved in the small intestinal reperfusion dam‌age. Acta Physiol Scand 1985; 124: 581-9. https://doi.org/10.1111/j.1748-1716.1985.tb00051.x##Tavafi M, Ahmadvand H, Tamjidipour A, Hasanvand A. Ros‌marinic acid ameliorates renal ischemia reperfusion damage in rats. J Nephropharmacol 2020; 9: e15. https://doi.org/10.34172/npj.2020.15##Urfalioğlu A, Yazar FM, Bilal B, Tolun Fİ, Öksüz H, Boran ÖF, et al. The effect of p-coumaric acid and ellagic acid on the liver and lungs in a rat model of sepsis. Asian Biomed 2017; 11: 217-25.##Yeh CT, Ching LC, Yen GC. Inducing gene expression of car‌diac antioxidant enzymes by dietary phenolic acids in rats. J Nutr Biochem 2009; 20: 163-71. https://doi.org/10.1016/j.jnutbio.2008.01.005 ##Younes M, Mohr A, Schoenberg M, Schildberg F. Inhibition of lipid peroxidation by superoxide dismutase following regional intestinal ischemia and reperfusion. Res Exp Med 1987; 187: 9-17. https://doi.org/10.1007/BF01854963##Yuan GJ, Ma JC, Gong ZJ, Sun XM, Zheng SH, Li X. Mod‌ulation of liver oxidant-antioxidant system by ischemic preconditioning during ischemia/reperfusion injury in rats. World J Gastroenterol 2005; 11: 1825. https://doi.org/10.3748/wjg.v11.i12.1825## ##

Time course study of ERK1/2 activity and cell viability in lipopolysaccharide challenged PC12 cells 2 2 Introduction: Extracellular signal-regulated kinase 1 and 2 (ERK1/2) are important members of mitogen-activated protein kinases (MAPK), which are actively involved in the shaping of cellular responses to different stimuli; however, these responses are somehow contradicting. It is believed that time is a crucial factor in the determination of these effects. Therefore, the present work was designed to obtain a more vivid view about the effect of time on ERK activity and its relation to cell viability. Methods: In the first step, we challenged cultured PC12 cells with different doses of lipopolysaccharides (LPS) for different time intervals (3, 6, 24 and 48h) and the cell viability was checked by MTT test. Thereafter, we cultured the cells in 6-well plates and treated them with the effective dose (10μg/ml) for the abovementioned intervals and the level of ERK phosphorylation, as the active form, was assessed in the Western blotting analysis. Results: The results showed that treating cells with 10μg/ml LPS reduces cell viability after 48h. While being ineffective in shorter periods of time, ERK activity has a fluctuating trend, so that it reaches the highest level at 6h, thereafter it declines to the lowest level at 24h and partially increases again at 48h. Conclusion: These results imply that time is a determinant factor in the activity of ERK and single-point assessments may result in misinterpretation. 76 82 2020/04/242020/06/152020/07/222020/07/82020/02/82019/08/252020/03/112020/04/16 1399/1/28 2020/07/252020/12/12020/10/272020/10/272020/08/152020/10/182020/08/42020/10/3 1399/7/12 Pegah Javadpour Pegah Javadpour Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran pegah.javadpour@sbmu.ac.ir Sahar Askari Sahar Askari Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran saharaskari@sbmu.ac.ir Fateme Azizi Fateme Azizi School of advanced medical technologies, Tehran university of medical sciences, Tehran, Iran Iran azizifateme14@gmail.com Rasoul Ghasemi Rasoul Ghasemi Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran Iran rghasemi60@sbmu.ac.ir Inflammation Time factors ERK1/ 2 MAPK Lipopolysaccharides PC12 cells. Abbasnejad Z, Nasseri B, Zardooz H, Ghasemi R. Time-course study of high fat diet induced alterations in spatial memory, hippocampal JNK, P38, ERK and Akt activity. Metab Brain Dis 2019; 34: 659-73. https://doi.org/10.1007/s11011-018-0369-1##Chen MJ, Ramesha S, Weinstock LD, Gao T, Ping L, Xiao H, et al. Microglial ERK signaling is a critical regu-lator of pro-inflammatory immune responses in Alz‌heimer’s disease. bioRxiv 2019; 798215. https://doi.org/10.1101/798215##Cheng P, Alberts I, Li X. The role of ERK1/2 in the regulation of proliferation and differentiation of astrocytes in devel‌oping brain. Int J Dev Neurosci 2013; 31: 783-9. https://doi.org/10.1016/j.ijdevneu.2013.09.008##Cruz CD, Cruz F. The ERK 1 and 2 pathway in the nervous sys‌tem: from basic aspects to possible clinical applications in pain and visceral dysfunction. Curr Neuropharmacol 2007; 5: 244-52. https://doi.org/10.2174/157015907782793630##Deng Z, Sui G, Rosa PM, Zhao W. Radiation-induced c-Jun activation depends on MEK1-ERK1/2 signaling pathway in microglial cells. PLoS One 2012; 7: e36739. https://doi.org/10.1371/journal.pone.0036739##Fields J, Cisneros IE, Borgmann K, Ghorpade A. Extracellu‌lar regulated kinase 1/2 signaling is a critical regulator of interleukin-1β-mediated astrocyte tissue inhibitor of metal‌loproteinase-1 expression. PLoS One 2013; 8: e56891. https://doi.org/10.1371/journal.pone.0056891##Jeong YH, Li W, Go Y, Oh YC. Atractylodis rhizoma alba at‌tenuates neuroinflammation in BV2 microglia upon LPS stimulation by inducing HO-1 activity and inhibiting NF-κB and MAPK. Int J Mol Sci 2019; 20: 4015. https://doi.org/10.3390/ijms20164015##Kim HK. Role of ERK/MAPK signalling pathway in anti-in‌flammatory effects of Ecklonia cava in activated human mast cell line-1 cells. Asian Pac J Trop Med 2014; 7: 703-8. https://doi.org/10.1016/S1995-7645(14)60120-6##Kim S, Lee MS, Lee B, Gwon WG, Joung EJ, Yoon NY, et al. Anti-inflammatory effects of sargachromenol-rich ethano‌lic extract of Myagropsis myagroides on lipopolysaccha‌ride-stimulated BV-2 cells. BMC Complement Altern Med 2014; 14: 1-12. https://doi.org/10.1186/1472-6882-14-231##Kurosawa M, Numazawa S, Tani Y, Yoshida T. ERK sig‌naling mediates the induction of inflammatory cytokines by bufalin in human monocytic cells. Am J Physiol Cell Physiol 2000; 278: C500-8. https://doi.org/10.1152/ajp‌cell.2000.278.3.C500##Lee IS, Ryu DK, Lim J, Cho S, Kang BY, Choi HJ. Artesu‌nate activates Nrf2 pathway-driven anti-inflammatory potential through ERK signaling in microglial BV2 cells. Neurosci lett 2012; 509: 17-21. https://doi.org/10.1016/j.neulet.2011.12.034##Li F, Omori N, Sato K, Jin G, Nagano I, Manabe Y, et al. Coordinate expression of survival p-ERK and proapop‌totic cytochrome c signals in rat brain neurons after tran‌sient MCAO. Brain Res 2002; 958: 83-8. https://doi.org/10.1016/S0006-8993(02)03465-0##Lim HS, Kim YJ, Kim BY, Jeong SJ. Bakuchiol suppresses inflammatory responses via the downregulation of the p38 MAPK/ERK signaling pathway. Int J Mol Sci 2019; 20: 3574. https://doi.org/10.3390/ijms20143574##Maeng YS, Min JK, Kim JH, Yamagishi A, Mochizuki N, Kwon JY, et al. ERK is an anti-inflammatory signal that suppresses expression of NF-kappaB-dependent inflamma‌tory genes by inhibiting IKK activity in endothelial cells. Cell Signal 2006; 18: 994-1005. https://doi.org/10.1016/j.cellsig.2005.08.007##Park GH, Jeon SJ, Ryu JR, Choi MS, Han SH, Yang SI, et al. Essential role of mitogen-activated protein kinase path‌ways in protease activated receptor 2-mediated nitric-oxide production from rat primary astrocytes. Nitric Oxide 2009; 21: 110-9. https://doi.org/10.1016/j.niox.2009.05.007##Parthasarathy G, Philipp MT. The MEK/ERK pathway is the primary conduit for Borrelia burgdorferi-induced in‌flammation and P53-mediated apoptosis in oligodendro‌cytes. Apoptosis 2014; 19: 76-89. https://doi.org/10.1007/s10495-013-0913-8##Permpoonputtana K, Porter JE, Govitrapong P. Calcitonin gene-related peptide mediates an inflammatory response in Schwann cells via cAMP-dependent ERK signaling cas‌cade. Life Sci 2016; 144: 19-25. https://doi.org/10.1016/j.lfs.2015.11.015##Sabio G, Davis RJ. TNF and MAP kinase signalling path‌ways. Semin Immunol 2014; 26: 237-245. https://doi.org/10.1016/j.smim.2014.02.009##Schuh K, Pahl A. Inhibition of the MAP kinase ERK protects from lipopolysaccharide-induced lung injury. Biochem Pharmacol 2009; 77: 1827-34. https://doi.org/10.1016/j.bcp.2009.03.012##Senger K, Pham VC, Varfolomeev E, Hackney JA, Corzo CA, Collier J, et al. The kinase TPL2 activates ERK and p38 signaling to promote neutrophilic inflammation. Sci Signal 2017; 10. https://doi.org/10.1126/scisignal.aah4273##Seo SW, Lee D, Minematsu H, Kim AD, Shin M, Cho SK, et al. Targeting extracellular signal-regulated kinase (ERK) signaling has therapeutic implications for inflammatory os‌teolysis. Bone 2010; 46: 695-702. https://doi.org/10.1016/j.bone.2009.10.032##Shao J, Liu T, Xie QR, Zhang T, Yu H, Wang B, et al. Adjudin attenuates lipopolysaccharide (LPS)-and ischemia-induced microglial activation. J Neuroimmunol 2013; 254: 83-90. https://doi.org/10.1016/j.jneuroim.2012.09.012##Stanciu M, Wang Y, Kentor R, Burke N, Watkins S, Kress G, et al. Persistent activation of ERK contributes to gluta‌mate-induced oxidative toxicity in a neuronal cell line and primary cortical neuron cultures. J Biol Chem 2000; 275: 12200-6. https://doi.org/10.1074/jbc.275.16.12200##Sun J, Shigemi H, Tanaka Y, Yamauchi T, Ueda T, Iwasaki H. Tetracyclines downregulate the production of LPS-induced cytokines and chemokines in THP-1 cells via ERK, p38, and nuclear factor-kappaB signaling pathways. Biochem Biophys Rep 2015; 4: 397-404. https://doi.org/10.1016/j.bbrep.2015.11.003##Szelenyi ER, Urso ML. Time-course analysis of injured skel‌etal muscle suggests a critical involvement of ERK1/2 sig‌naling in the acute inflammatory response. Muscle Nerve 2012; 45: 552-61. https://doi.org/10.1002/mus.22323##Thalhamer T, McGrath M, Harnett M. MAPKs and their rel‌evance to arthritis and inflammation. Rheumatology 2008; 47: 409-14. https://doi.org/10.1093/rheumatology/kem297##Valledor AF, Comalada M, Xaus J, Celada A. The differential time-course of extracellular-regulated kinase activity cor‌relates with the macrophage response toward proliferation or activation. J Biol Chem 2000; 275: 7403-9. https://doi.org/10.1074/jbc.275.10.7403##Verhaeghe C, Remouchamps C, Hennuy B, Vanderplasschen A, Chariot A, Tabruyn SP, et al. Role of IKK and ERK pathways in intrinsic inflammation of cystic fibrosis air‌ways. Biochem Pharmacol 2007; 73: 1982-94. https://doi.org/10.1016/j.bcp.2007.03.019##Wang YJ, Zheng YL, Lu J, Chen GQ, Wang XH, Feng J, et al. Purple sweet potato color suppresses lipopolysaccha‌ride-induced acute inflammatory response in mouse brain. Neurochem Int 2010; 56: 424-30. https://doi.org/10.1016/j.neuint.2009.11.016##Weinstein JR, Zhang M, Kutlubaev M, Lee R, Bishop C, An‌dersen H, et al. Thrombin-induced regulation of CD95(‌Fas) expression in the N9 microglial cell line: evidence for involvement of proteinase-activated receptor(1) and extra‌cellular signal-regulated kinase 1/2. Neurochem Res 2009; 34: 445-52. https://doi.org/10.1007/s11064-008-9803-9##Wuyts WA, Vanaudenaerde BM, Dupont LJ, Demedts MG, Verleden GM. Involvement of p38 MAPK, JNK, p42/p44 ERK and NF-kappaB in IL-1beta-induced chemok‌ine release in human airway smooth muscle cells. Respir Med 2003; 97: 811-7. https://doi.org/10.1016/S0954-6111(03)00036-2##Xia Q, Hu Q, Wang H, Yang H, Gao F, Ren H, et al. Induction of COX-2-PGE2 synthesis by activation of the MAPK/ERK pathway contributes to neuronal death triggered by TDP-43-depleted microglia. Cell Death Dis 2015; 6: e1702. https://doi.org/10.1038/cddis.2015.69##Zhang X, Zhang H, Shao H, Xue Q, Yu B. ERK MAP ki‌nase activation in spinal cord regulates phosphorylation of Cdk5 at serine 159 and contributes to peripheral inflam‌mation induced pain/hypersensitivity. PLoS One 2014; 9: e87788. https://doi.org/10.1371/journal.pone.0087788##Zhao H, Wang SL, Qian L, Jin JL, Li H, Xu Y, et al. Diammo‌nium glycyrrhizinate attenuates Aβ1-42-induced neuroin‌flammation and regulates MAPK and NF-κB pathways in vitro and in vivo. CNS Neurosci Ther 2013; 19: 117-24. https://doi.org/10.1111/cns.12043##Zhou QL, Wang TY, Li M, Shang YX. Alleviating airway in‌flammation by inhibiting ERK-NF-κB signaling pathway by blocking Kv1. 3 channels. Int Immunopharmacol 2018; 63: 110-8. https://doi.org/10.1016/j.intimp.2018.07.009##Zhuang ZY, Gerner P, Woolf CJ, Ji RR. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 2005; 114: 149-59. https://doi.org/10.1016/j.pain.2004.12.022## ##

Atorvastatin enhances the antitumor activity of tamoxifen in B16f10 mouse melanoma cell lines 2 2 Introduction: Tamoxifen has been used in the treatment of metastatic malignant melanoma more common with other agents in the combined therapy. Up-regulated activity of the mevalonate pathway has been shown in a range of different cancers. Atorvastatin is the most commonly used statin approved for cholesterol reduction by inhibiting the mevalonate pathway and has been shown to inhibit tumor growth. In the present study, we used atorvastatin and tamoxifen combination therapy on B16f10 mouse melanoma cell lines to study whether atorvastatin could increase the sensitivity of melanoma cells to the chemotherapeutic agent such as tamoxifen. Methods: The cell line was treated with different concentrations of tamoxifen and/or atorvastatin for 24 and 48h and the effects of treatment on p53 and RhoA were investigated using quantitative RT-PCR. Results: The combination of atorvastatin and tamoxifen resulted in a potentiation antitumor effect via up-regulation of p53 and down-regulation of RhoA expression against melanoma tumors in vitro. Furthermore, we demonstrated the combination of atorvastatin with tamoxifen could reduce tamoxifen dose to minimize possible detrimental side effects in melanoma. Conclusion: Our results suggested that atorvastatin as a combined therapy with tamoxifen may provide a new approach for improving the efficacy and treating against melanoma cancer but needs further exploration in clinical trials. 83 91 2020/04/242020/06/152020/07/222020/07/82020/02/82019/08/252020/03/112020/04/162020/05/25 1399/3/5 2020/07/252020/12/12020/10/272020/10/272020/08/152020/10/182020/08/42020/10/32020/09/15 1399/6/25 Maryam Malek Maryam Malek Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Iran Malek.maryam@med.mui.ac.ir Maedeh Ghasemi Maedeh Ghasemi Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Iran ghasemi.m@med.mui.ac.ir Golnaz Vaseghi Golnaz Vaseghi Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran Iran golnazvaseghi@yahoo.com Ahmad Ghasemi Ahmad Ghasemi Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Iran Ahmad@resident.mui.ac.ir Hajar Naji Esfahani Hajar Naji Esfahani Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran Iran naji.hajar2016@gmail.com Nasim Dana Nasim Dana Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran Iran nasim.dana@mui.ac.ir Shaghayegh Haghjooy Javanmard Shaghayegh Haghjooy Javanmard Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran Iran sh_haghjoo@med.mui.ac.ir Tamoxifen Atorvastatin p53 RhoA Melanoma. Altwairgi AK. Statins are potential anticancerous agents. Oncol Rep 2015; 33: 1019-39. https://doi.org/10.3892/or.2015.3741 ##Armitage J. The safety of statins in clinical practice. Lan‌cet 2007; 370: 1781-90. https://doi.org/10.1016/S0140-6736(07)60716-8##Barbalata CI, Tefas LR, Achim M, Tomuta I, Porfire AS. Statins in risk-reduction and treatment of cancer. World J Clin Oncol 2020; 11: 573. https://doi.org/10.5306/wjco.v11.i8.573##Beckwitt CH, Brufsky A, Oltvai ZN, Wells A. Statin drugs to reduce breast cancer recurrence and mortality. Breast Cancer Res 2018; 20: 144. https://doi.org/10.1186/s13058-018-1066-z##Clayton NS, Ridley AJ. Targeting Rho GTPase signaling net‌works in cancer. Front Cell Dev Biol 2020; 8: 222. https://doi.org/10.3389/fcell.2020.00222 ##Collisson EA, Carranza DC, Chen IY, Kolodney MS. Iso‌prenylation is necessary for the full invasive potential of RhoA overexpression in human melanoma cells. J Invest Dermatol 2002; 119: 1172-6. https://doi.org/10.1046/j.1523-1747.2002.19519.x##Collisson EA, Kleer C, Wu M, De A, Gambhir SS, Merajver SD, et al. Atorvastatin prevents RhoC isoprenylation, inva‌sion, and metastasis in human melanoma cells. Mol Cancer Ther 2003; 2: 941-8.##Demierre MF, Higgins PD, Gruber SB, Hawk E, Lippman SM. Statins and cancer prevention. Nat Rev Cancer 2005; 5: 930-42. https://doi.org/10.1038/nrc1751##Depasquale I, Wheatley DN. Action of Lovastatin (Mevino‌lin) on an in vitro model of angiogenesis and its co-culture with malignant melanoma cell lines. Cancer Cell Int 2006; 6: 1-2. https://doi.org/10.1186/1475-2867-6-9##Fatehi Hassanabad A. Current perspectives on statins as po‌tential anti-cancer therapeutics: clinical outcomes and un‌derlying molecular mechanisms. Transl Lung Cancer Res 2019; 8: 692-9. https://doi.org/10.21037/tlcr.2019.09.08##Freed-Pastor WA, Mizuno H, Zhao X, Langerød A, Moon SH, Rodriguez-Barrueco R, et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate path‌way. Cell 2012; 148: 244-58. https://doi.org/10.1016/j.cell.2011.12.017##Freeman SR, Drake AL, Heilig LF, Graber M, McNealy K, Schilling LM, et al. Statins, fibrates, and melanoma risk: a systematic review and meta-analysis. J Natl Cancer Inst 2006; 98: 1538-46. https://doi.org/10.1093/jnci/djj412##Fritz G, Kaina B. Rho GTPases: promising cellular targets for novel anticancer drugs. Curr Cancer Drug Targets 2006; 6: 1-4. https://doi.org/10.2174/156800906775471752##Glynn SA, O’Sullivan D, Eustace AJ, Clynes M, O’Donovan N. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, simvastatin, lovastatin and mevastatin inhibit proliferation and invasion of melanoma cells. BMC Can‌cer 2008; 8: 9. https://doi.org/10.1186/1471-2407-8-9##Guy Jr GP, Thomas CC, Thompson T, Watson M, Massetti GM, Richardson LC. Vital signs: melanoma incidence and mortality trends and projections-United States, 1982-2030. MMWR Morb Mortal Wkly Rep 2015; 64: 591.##Haga RB, Ridley AJ. Rho GTPases: regulation and roles in cancer cell biology. Small GTPases 2016; 7: 207-21.https://doi.org/10.1080/21541248.2016.1232583##Hayashi M, Sakata M, Takeda T, Tahara M, Yamamoto T, Minekawa R, et al. Hypoxia up-regulates hypoxia-induc‌ible factor-1α expression through RhoA activation in tro‌phoblast cells. J Clin Endocrinol Metab 2005; 90: 1712-9. https://doi.org/10.1210/jc.2004-1547##Hultsch S, Kankainen M, Paavolainen L, Kovanen RM, Ikonen E, Kangaspeska S, et al. Association of tamoxifen resistance and lipid reprogramming in breast cancer. BMC Cancer 2018; 18: 850. https://doi.org/10.1186/s12885-018-4757-z##Ibrahim AB, Zaki HF, Ibrahim WW, Omran MM, Shouman SA. Evaluation of tamoxifen and simvastatin as the com‌bination therapy for the treatment of hormonal dependent breast cancer cells. Toxicol Rep 2019; 6: 1114-26. https://doi.org/10.1016/j.toxrep.2019.10.016##Ingallina E, Sorrentino G, Bertolio R, Lisek K, Zannini A, Az‌zolin L, et al. Mechanical cues control mutant p53 stability through a mevalonate-RhoA axis. Nat Cell Biol 2018; 20: 28-35. https://doi.org/10.1038/s41556-017-0009-8##Ji L, Liu C, Yuan Y, Gao H, Tang Z x, Yang Z, et al. Key roles of Rho GTPases, YAP, and Mutant P53 in anti-neoplastic effects of statins. Fund Clin Pharmacol 2020; 34: 4-10. https://doi.org/10.1111/fcp.12495##Karlic H, Thaler R, Gerner C, Grunt T, Proestling K, Haider F, et al. Inhibition of the mevalonate pathway affects epi‌genetic regulation in cancer cells. Cancer Genet 2015; 208: 241-52. https://doi.org/10.1016/j.cancergen.2015.03.008##Lagadec C, Adriaenssens E, Toillon R, Chopin V, Romon R, Van Coppenolle F, et al. Tamoxifen and TRAIL synergis‌tically induce apoptosis in breast cancer cells. Oncogene 2008; 27: 1472-7. https://doi.org/10.1038/sj.onc.1210749##Law M, Rudnicka AR. Statin safety: a systematic review. Am J Card 2006; 97: S52-60. https://doi.org/10.1016/j.amj‌card.2005.12.010##Liang Z, Li W, Liu J, Li J, He F, Jiang Y, et al. Simvastatin suppresses the DNA replication licensing factor MCM7 and inhibits the growth of tamoxifen-resistant breast can‌cer cells. Sci Rep 2017; 7: 1-11. https://doi.org/10.1038/srep41776##Malenda A, Skrobanska A, Issat T, Winiarska M, Bil J, Oleszczak B, et al. Statins impair glucose uptake in tumor cells. Neoplasia 2012; 14: 311-23. https://doi.org/10.1593/neo.12444##Minichsdorfer C, Hohenegger M. Autocrine amplification loop in statin-induced apoptosis of human melanoma cells. Br J Pharmacol 2009; 157: 1278-90. https://doi.org/10.1111/j.1476-5381.2009.00298.x##Noguchi Y, Nakamura S, Yasuda T, Kitagawa M, Kohn LD, Saito Y, et al. Newly synthesized Rho A, not Ras, is iso‌prenylated and translocated to membranes coincident with progression of the G1 to S phase of growth-stimulated rat FRTL-5 cells. J Biol Chem 1998; 273: 3649-53. https://doi.org/10.1074/jbc.273.6.3649##Parrales A, Thoenen E, Iwakuma T. The interplay between mutant p53 and the mevalonate pathway. Cell Death Dif‌fer 2018; 25: 460-70. https://doi.org/10.1038/s41418-017-0026-y##Porter AP, Papaioannou A, Malliri A. Deregulation of Rho GTPases in cancer. Small GTPases 2016; 7: 123-38. https://doi.org/10.1080/21541248.2016.1173767##Rigel DS, Carucci JA. Malignant melanoma: prevention, ear‌ly detection, and treatment in the 21st century. CA Can‌cer J Clin 2000; 50: 215-36. https://doi.org/10.3322/canj‌clin.50.4.215##Ring A, Dowsett M. Mechanisms of tamoxifen resistance. Endocr Relat Cancer 2004; 11: 643-58. https://doi.org/10.1677/erc.1.00776##Rivlin N, Brosh R, Oren M, Rotter V. Mutations in the p53 tumor suppressor gene: important milestones at the vari‌ous steps of tumorigenesis. Genes Cancer 2011; 2: 466-74. https://doi.org/10.1177/1947601911408889##Rusthoven J. The evidence for tamoxifen and chemotherapy as treatment for metastatic melanoma. Eur J Cancer 1998; 34: 31-6. https://doi.org/10.1016/S0959-8049(97)10162-9##Saito A, Saito N, Mol W, Furukawa H, Tsutsumida A, Oya‌ma A, et al. Simvastatin inhibits growth via apoptosis and the induction of cell cycle arrest in human melanoma cells. Melanoma Res 2008; 18: 85-94. https://doi.org/10.1097/CMR.0b013e3282f60097##Stanisavljevic D, Petrovic I, Vukovic V, Schwirtlich M, Gredic M, Stevanovic M, et al. SOX14 activates the p53 signaling pathway and induces apoptosis in a cervi‌cal carcinoma cell line. PloS One 2017; 12: e0184686.https://doi.org/10.1371/journal.pone.0184686##Stine JE, Guo H, Sheng X, Han X, Schointuch MN, Gilliam TP, et al. The HMG-CoA reductase inhibitor, simvasta‌tin, exhibits anti-metastatic and anti-tumorigenic effects in ovarian cancer. Oncotarget 2016; 7: 946. https://doi.org/10.18632/oncotarget.5834##Tarhini AA, Agarwala SS. Cutaneous melanoma: available therapy for metastatic disease. Dermatol Ther 2006; 19: 19-25. https://doi.org/10.1111/j.1529-8019.2005.00052.x##Tiwary R, Yu W, Linda AD, Sanders BG, Kline K. Target‌ing cholesterol-rich microdomains to circumvent tamox‌ifen-resistant breast cancer. Breast Cancer Res 2011; 13: R120. https://doi.org/10.1186/bcr3063##Toma S, Ugolini D, Palumbo R. Tamoxifen in the treatment of metastatic malignant melanoma: still a controversy? Int J Oncol 1999; 15: 321-58. https://doi.org/10.3892/ijo.15.2.321##Tsubaki M, Takeda T, Obata N, Kawashima K, Tabata M, Imano M, et al. Combination therapy with dacarbazine and statins improved the survival rate in mice with metastatic melanoma. J Cell Physiol 2019; 234: 17975-89. https://doi.org/10.1002/jcp.28430##Tutuska K, Parrilla-Monge L, Di Cesare E, Nemajerova A, Moll UM. Statin as anti-cancer therapy in autochthonous T-lymphomas expressing stabilized gain-of-function mu‌tant p53 proteins. Cell Death Dis 2020; 11: 1-12. https://doi.org/10.1038/s41419-020-2466-4##Villalonga P, Villalonga P, Ridley AJ. Rho GTPases and cell cycle control. Growth Factor 2006; 24: 159-64.https://doi.org/10.1080/08977190600560651##von Schuckmann LA, Khosrotehrani K, Ghiasvand R, Hughes MC, van der Pols JC, Malt M, et al. Statins may reduce disease recurrence in patients with ul‌cerated primary melanoma. Br J Dermatol 2020.https://doi.org/10.1111/bjd.19012##Watson M, Holman DM, Maguire-Eisen M. Ultraviolet ra‌diation exposure and its impact on skin cancer risk. InSeminars in Oncology Nursing 2016; 32: 241-254.https://doi.org/10.1016/j.soncn.2016.05.005##Yang AS, Chapman PB. The history and future of chemother‌apy for melanoma. Hematol Oncol Clin 2009; 23: 583-97. https://doi.org/10.1016/j.hoc.2009.03.006## ##

Fear stress in computer games caused brain waves, oxytocin and brain-derived neurotrophic factor changes among woman 2 2 Introduction: Stress and fear caused by computer games have been shown to have various effects on the cognitive system. This work was aimed to investigate the effects of short-time horror computer games on cognitive indicators. Methods: A total of twenty female subjects were recruited and divided into experimental and control groups. All required tests were performed before and after the intervention (playing or watching horror game) on the control and experimental groups. The saliva samples were collected before and after the intervention to measure levels of cortisol and alpha-amylase. Also, blood was taken before and during the game from each subject to evaluate plasma levels of oxytocin and brain-derived neurotrophic factor. The Brain waveforms were acquired by Emotive brain signal recording device before and after the intervention. Data analysis was conducted using R and MATLAB software. Results: The cortisol and alpha-amylase levels were shown to significantly increase after the horror game playing. Also, the levels of oxytocin were significantly higher after the experimentation. The levels of brain-derived neurotrophic factor were displayed to reduce after the experimentation. The results of the brainwave analysis revealed that the average stress index was significantly higher, while the average attention index was lower after playing the game. No significant difference in the study variables was observed in the control group. Conclusion: Horror computer games may have adverse effects on the activity of the stress system in the central nervous system. Fear-induced stress was shown to relatively undermine some cognitive elements. 92 98 2020/04/242020/06/152020/07/222020/07/82020/02/82019/08/252020/03/112020/04/162020/05/252020/04/11 1399/1/23 2020/07/252020/12/12020/10/272020/10/272020/08/152020/10/182020/08/42020/10/32020/09/152020/10/3 1399/7/12 Hamed Aliyari Hamed Aliyari Center for Human-Engaged Computing, Kochi University of Technology, Kochi, Japan Japan hamedaliyary@gmail.com Hedayat Sahraei Hedayat Sahraei Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran Iran h.sahrae@bmsu.ac.ir Sahar Golabi Sahar Golabi Abadan Faculty of Medical Sciences, Abadan, Iran Iran sgolabister@gmail.com Masoomeh Kazemi Masoomeh Kazemi Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran Iran s.golabi@aums.ac.ir Behrouz Minaei-Bidgoli Behrouz Minaei-Bidgoli School of Computer Engineering, University of Science and Technology, Tehran, Iran Iran bminaee@gmail.com Mohammad Reza Daliri Mohammad Reza Daliri Department of Electrical Engineering, University of Science and Technology, Tehran, Iran Iran dallir@iust.ac.ir Hassan Agaei Hassan Agaei Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran Iran sayyedagha313@gmail.com Zahra Dehghanimohammadabadi Zahra Dehghanimohammadabadi Department of Statistics, Faculty of Mathematical Sciences, AL Zahra University, Tehran, Iran Iran zh.dehghani41@gmail.com Mehdi Hadipoor Mehdi Hadipoor Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran Iran m.hadipoor@gmail.com Cortisol Alpha-amylase Oxytocin Horror computer game Brain-derived neurotrophic factor. Aliyari H, Hosseinian S, Sahraei H, Menhaj M. Effect of proximity to high-voltage fields: results of the neural network model and experimental model with macaques. Int J Environ Sci Technol 2019a; 16: 4315-26. https://doi.org/10.1007/s13762-018-1830-8##Aliyari H, Hosseinian SH, Menhaj MB, Sahraei H. Analysis of the effects of high-voltage transmission line on human stress and attention through electroencephalography (EEG). Iran J Sci Technol Trans Electr Eng 2019b: 1-8. https://doi.org/10.1007/s40998-018-0151-8##Aliyari H, Kazemi M, Tekieh E, Salehi M, Sahraei H, Daliri MR, et al. The effects of fifa 2015 computer games on changes in cognitive, hormonal and brain waves functions of young men volunteers. Basic Clin Neurosci 2015; 6: 193.##Aliyari H, Sahraei H, Daliri MR, Minaei-Bidgoli B, Kazemi M, Agaei H, et al. The beneficial or harmful effects of computer game stress on cognitive functions of players. Basic Clin Neurosci 2018; 9: 177-86. https://doi.org/10.29252/nirp.bcn.9.3.177##Aliyari H, Sahraei H, Erfani M, Mohammadi M, Kazemi M, Daliri MR, et al. Changes in cognitive functions following violent and football video games in young male volunteers by studying brain waves. Basic Clin Neurosci 2020; 11: 279-288.##Aliyari H, Sahraei H, Erfani M, Tekieh E, Salehi M, Kazemi M, et al. The impacts of video games on cognitive function and cortisol levels in young female volunteers. J Exp Clin Neurosci 2019c; 6.##Anderson CA. An update on the effects of playing violent video games. J Adolesc 2004; 27: 113-22. https://doi.org/10.1016/j.adolescence.2003.10.009##Anderson CA, Bushman BJ. Effects of violent video games on aggressive behavior, aggressive cognition, aggressive affect, physiological arousal, and prosocial behavior: a meta-analytic review of the scientific literature. Psychol Sci 2001; 12: 353-9. https://doi.org/10.1111/1467-9280.00366##Angelucci F, Brene S, Mathe A. BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry 2005; 10: 345-52. https://doi.org/10.1038/sj.mp.4001637##Bos DP, Reuderink B, van de Laar B, Gürkök H, Mühl C, Poel M, et al. Brain-computer interfacing and games. London: Springer, 2010.##Dickerson SS,Kemeny ME. Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. Psychol Bull 2004; 130: 355. https://doi.org/10.1037/0033-2909.130.3.355##Driscoll I, Hamilton DA, Yeo RA, Brooks WM, Sutherland R J. Virtual navigation in humans: the impact of age, sex, and hormones on place learning. Horm Behav 2005; 47: 326-35. https://doi.org/10.1016/j.yhbeh.2004.11.013##Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science 2012; 338: 68-72. https://doi.org/10.1126/science.1222939##Gordon I, Zagoory-Sharon O, Leckman JF, Feldman R. Oxytocin, cortisol, and triadic family interactions. Physiol Behav 2010; 101: 679-84. https://doi.org/10.1016/j.physbeh.2010.08.008##Griffiths MD. The educational benefits of videogames. Educ Health 2002; 20: 47-51.##Guastella AJ, Hickie IB. Guastella AJ, Hickie IB. Oxytocin treatment, circuitry, and autism: a critical review of the literature placing oxytocin into the autism context. Biol Psychiatry 2016; 79: 234-42. https://doi.org/10.1016/j.biopsych.2015.06.028##Haddad JJ, Saadé NE, Safieh-Garabedian B. Cytokines and neuro-immune-endocrine interactions: a role for the hypothalamic-pituitary-adrenal revolving axis. J Neuroimmunol 2002; 133: 1-9. https://doi.org/10.1016/S0165-5728(02)00357-0##Hassan A, Qibing C, Tao J, Bing-Yang L, Nian L, Li S, et al. Effects of plant activity on mental stress in young adults. HortScience 2018; 53: 104-9. https://doi.org/10.21273/HORTSCI12447-17##Haynes JD, Rees G. Decoding mental states from brain activity in humans. Nat Rev Neurosci 2006; 7: 523-34. https://doi.org/10.1038/nrn1931##Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U. Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol Psychiatry 2003; 54: 1389-98. https://doi.org/10.1016/S0006-3223(03)00465-7##Hunter RG, McCarthy KJ, Milne TA, Pfaff DW, McEwen BS. Regulation of hippocampal H3 histone methylation by acute and chronic stress. Proc Natl Acad Sci U S A 2009; 106: 20912-7. https://doi.org/10.1073/pnas.0911143106##Ivory JD, Kalyanaraman S. The effects of technological advancement and violent content in video games on players’ feelings of presence, involvement, physiological arousal, and aggression. J Commun 2007; 57: 532-55. https://doi.org/10.1111/j.1460-2466.2007.00356.x ##Krepki R, Blankertz B, Curio G, Müller KR. The Berlin Brain-Computer Interface (BBCI)-towards a new communication channel for online control in gaming applications. Multimed Tools Appl 2007; 33: 73-90. https://doi.org/10.1007/s11042-006-0094-3##Lu B, Nagappan G, Guan X, Nathan PJ, Wren P. BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci 2013; 14: 401-16. https://doi.org/10.1038/nrn3505##Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 2009; 10: 434-45. https://doi.org/10.1038/nrn2639##Ma L, Liu J, Li N, Wang J, Duan Y, Yan J, et al. Oxidative stress in the brain of mice caused by translocated nanoparticulate TiO2 delivered to the abdominal cavity. Biomaterials 2010; 31: 99-105. https://doi.org/10.1016/j.biomaterials.2009.09.028##Nater UM, La Marca R, Florin L, Moses A, Langhans W, Koller MM, Ehlert U. Stress-induced changes in human salivary alpha-amylase activity-associations with adrenergic activity. Psychoneuroendocrinology 2006; 31: 49-58. https://doi.org/10.1016/j.psyneuen.2005.05.010##Nater UM, Rohleder N. Salivary alpha-amylase as a non-invasive biomarker for the sympathetic nervous system: current state of research. Psychoneuroendocrinology 2009; 34: 486-496. https://doi.org/10.1016/j.psyneuen.2009.01.014##Primack BA, Carroll MV, McNamara M, Klem ML, King B, Rich M, et al. Role of video games in improving health-related outcomes: a systematic review. Am J Prev Med 2012; 42: 630-8. https://doi.org/10.1016/j.amepre.2012.02.023##Russoniello CV, O’Brien K, Parks JM. The effectiveness of casual video games in improving mood and decreasing stress. J Cyber Ther Rehabil 2009; 2: 53-66.##Sharma R, Khera SH, Mohan AM, Gupta NI, Ray RB. Assessment of computer game as a psychological stressor. Indian J Physiol Pharmacol 2006; 50: 367.##Tan D, Nijholt A. Brain-computer interfaces and human-computer interaction. In: Brain-computer interfaces London: Springer, 2010, p. 3-19. https://doi.org/10.1007/978-1-84996-272-8_1##Tang WY, Fox J. Men’s harassment behavior in online video games: personality traits and game factors. Aggress Behav 2016; 42: 513-21. https://doi.org/10.1002/ab.21646##Ubilluz C, Delgado R, Marcillo D, Noboa T. Brain waves processing, analysis and acquisition to diagnose stress level in the work environment. In: World conference on information systems and technologies. Cham: Springer, 2018, p.859-66. https://doi.org/10.1007/978-3-319-77712-2_81 ##van Stegeren AH, Wolf OT, Kindt M. Salivary alpha amylase and cortisol responses to different stress tasks: impact of sex. Int J Psychophysiol 2008; 69: 33-40. https://doi.org/10.1016/j.ijpsycho.2008.02.008##Varga K, Kekecs Z. Oxytocin and cortisol in the hypnotic interaction. Int J Clin Exp Hypn 2014; 62: 111-28. https://doi.org/10.1080/00207144.2013.841494##Vasterling JJ, Brailey K, Constans JI, Sutker PB. Attention and memory dysfunction in posttraumatic stress disorder. Neuropsychology 1998; 12: 125. https://doi.org/10.1037/0894-4105.12.1.125##Yuen EY, Wei J, Liu W, Zhong P, Li X, Yan Z. Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex. Neuron 2012; 73: 962-77. https://doi.org/10.1016/j.neuron.2011.12.033## ##