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Open Access 01-06-2018 | Original Article

The effects of tramadol administration on hippocampal cell apoptosis, learning and memory in adult rats and neuroprotective effects of crocin

Authors: Farideh Baghishani, Abbas Mohammadipour, Hossain Hosseinzadeh, Mahmoud Hosseini, Alireza Ebrahimzadeh-bideskan

Published in: Metabolic Brain Disease | Issue 3/2018

Abstract

Tramadol, a frequently used pain reliever drug, present neurotoxic effects associated to cognitive dysfunction. Moreover, crocin has been reported to have neuroprotective effects. The aim of this study was to assess crocin’s capacity to protect learning, and memory abilities on tramadol-treated rats. A total of 35 rats were divided into five groups: Control, Saline, tramadol (50 mg/kg), tramadol + crocin(30 mg/kg), crocin groups and treated orally for 28 consecutive days. Morris water maze (MWM) and passive avoidance (PA) tests were done, followed by dissection of the rat’s brains for toluidine blue and TUNEL staining. In MWM test, tramadol group spent lower time and traveled shorter distance in the target quadrant (Q1) (P < 0.05). On the other side, the traveled distance in tramadol-crocin group was higher than tramadol (P < 0.05). In PA test, both the delay for entering the dark, and the total time spent in the light compartment decreased in tramadol comparing to the control group (P < 0.05), while it increased in tramadol-crocin compared with the tramadol group (P < 0.05). In tramadol-treated animals, the dark neurons (DNs) and apoptotic cells in CA1, CA3 and DG increased (P < 0.05), while concurrent intake of crocin decreased the number of DNs and apoptotic cells in these areas (P < 0.05). Crocin was able to improve learning and memory of tramadol-treated rats and also decreased DNs and apoptotic cells in the hippocampus. Considering these results, the potential capacity of crocin for decreasing side effects of tramadol on the nervous system is suggested.

Abdel-Salam OM, Youness ER, Khadrawy YA, Sleem AA (2016) Acetylcholinesterase, butyrylcholinesterase and paraoxonase 1 activities in rats treated with cannabis, tramadol or both. Asian Pac J Trop Med 9(11):1089–1094. https://doi.org/10.1016/j.apjtm.2016.09.009 CrossRefPubMed

Abdel-Zaher AO, Abdel-Rahman MS, ELwasei FM (2011) Protective effect of Nigella Sativa oil against tramadol-induced tolerance and dependence in mice: role of nitric oxide and oxidative stress. Neurotoxicology 32(6):725–733. https://doi.org/10.1016/j.neuro.2011.08.001 CrossRefPubMed

Ahmadi M, Rajaei Z, Hadjzadeh M, Nemati H, Hosseini M (2017) Crocin improves spatial learning and memory deficits in the Morris water maze via attenuating cortical oxidative damage in diabetic rats. Neurosci Lett 642:1–6. https://doi.org/10.1016/j.neulet.2017.01.049 CrossRefPubMed

Ahmadpour S, Haghir H (2011) Diabetes mellitus type 1 induces dark neuron formation in the dentate gyrus: a study by Gallyas' method and transmission electron microscopy. Romanian J Morphol Embryol 52(2):575–579

Akhondzadeh S, Tahmacebi-Pour N, Noorbala AA, Amini H, Fallah-Pour H, Jamshidi AH, Khani M (2005) Crocus sativus L. in the treatment of mild to moderate depression: a double-blind, randomized and placebo-controlled trial. Phytother Res 19:148–151. https://doi.org/10.1002/ptr.1647

Ataei ML, Ebrahimzadeh-bideskan AR (2014) The effects of nano-silver and garlic administration during pregnancy on neuron apoptosis in rat offspring hippocampus. Iranian journal of basic medical sciences 17:411PubMedPubMedCentral

Bagheri-abassi F, Alavi H, Mohammadipour A, Motejaded F, Ebrahimzadeh-bideskan A (2015) The effect of silver nanoparticles on apoptosis and dark neuron production in rat hippocampus. Iranian journal of basic medical sciences 18:644PubMedPubMedCentral

Bandegi AR, Rashidy-Pour A, Vafaei AA, Ghadrdoost B (2014) Protective effects of crocus Sativus L. extract and crocin against chronic-stress induced oxidative damage of brain, liver and kidneys in rats. Pharm Bull 4(Suppl 2):493–499. https://doi.org/10.5681/apb.2014.073 CrossRef

Bernabeu R, Schmitz P, Faillace MP, Izquierdo I, Medina JH (1996) Hippocampal cGMP and cAMP are differentially involved in memory processing of inhibitory avoidance learning. Neuroreport 7:585–588CrossRefPubMed

Bertaina-Anglade V, Enjuanes E, Morillon D, La Rochelle CD (2006) The object recognition task in rats and mice: a simple and rapid model in safety pharmacology to detect amnesic properties of a new chemical entity. J Pharmacol Toxicol Methods 54(2):99–105. https://doi.org/10.1016/j.vascn.2006.04.001 CrossRefPubMed

Boostani R, Derakhshan S (2012) Tramadol induced seizure: A 3-year study. Caspian J Intern Med 3(3):484–487

Candeletti S, Lopetuso G, Cannarsa R, Cavina C, Romualdi P (2006) Effects of prolonged treatment with the opiate tramadol on prodynorphin gene expression in rat. CNS. J Mol Neurosci 30(3):341–347. https://doi.org/10.1385/JMN:30:3:341 CrossRefPubMed

Carrillo-Munguía N, González-Trujano ME, Huerta M, Trujillo X, Díaz-Reval MI (2015) Tramadol and Tramadol. Biomed Res Int 2015 2015:1–9. https://doi.org/10.1155/2015/686424 CrossRef

Chahine N, Hanna J, Makhlouf H, Duca L, Martiny L, Chahine R (2013) Protective effect of saffron extract against doxorubicin cardiotoxicity in isolated rabbit heart. Pharm Biol 51(12):1564–1571. https://doi.org/10.3109/13880209.2013.802812 CrossRefPubMed

Collinson N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, Sur C, Smith A, Otu FM, Howell O, Atack JR, McKernan RM, Seabrook GR, Dawson GR, Whiting PJ, Rosahl TW (2002) Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the α5 subunit of the GABAAReceptor. J Neurosci 22(13):5572–5580CrossRefPubMed

Costa JT, Mele M, Baptista MS, Gomes JR, Ruscher K, Nobre RJ, de Almeida LP, Wieloch T, Duarte CB (2015) Gephyrin cleavage in in vitro brain ischemia decreases GABAA receptor clustering and contributes to neuronal death. Mol Neurobiol 53(6):1–15. https://doi.org/10.1007/s12035-015-9283-2 CrossRef

Cui K, Luo X, Xu K, Murthy MV (2004) Role of oxidative stress in neurodegeneration: recent developments in assay methods for oxidative stress and nutraceutical antioxidants. Prog Neuro-Psychopharmacol Biol Psychiatry 28(5):771–799. https://doi.org/10.1016/j.pnpbp.2004.05.023 CrossRef

Daulatzai MA (2013) Neurotoxic saboteurs: straws that break the hippo’s (hippocampus) back drive cognitive impairment and Alzheimer’s disease. Neurotox Res 24(3):407–459. https://doi.org/10.1007/s12640-013-9407-2 CrossRefPubMed

De Wit D, Koomen-Botman I (2012) Neonatal abstinence syndrome after maternal use of tramadol. Ned Tijdschr Geneeskd 157:A5610–A5610

Elkhateeb A, El Khishin I, Megahed O, Mazen F (2015) Effect of Nigella Sativa Linn oil on tramadol-induced hepato-and nephrotoxicity in adult male albino rats. Toxicol Rep 2:512–519. https://doi.org/10.1016/j.toxrep.2015.03.002 CrossRefPubMedPubMedCentral

Geromichalos GD, Lamari FN, Papandreou MA, Trafalis DT, Margarity M, Papageorgiou A, Sinakos Z (2012) Saffron as a source of novel acetylcholinesterase inhibitors: molecular docking and in vitro enzymatic studies. J Agric Food Chem 60(24):6131–6138. https://doi.org/10.1021/jf300589c CrossRefPubMed

Ghadrdoost B, Vafaei AA, Rashidy-Pour A, Hajisoltani R, Bandegi AR, Motamedi F, Haghighi S, Sameni HR, Pahlvan S (2011) Protective effects of saffron extract and its active constituent crocin against oxidative stress and spatial learning and memory deficits induced by chronic stress in rats. Eur J Pharmacol 667(1-3):222–229. https://doi.org/10.1016/j.ejphar.2011.05.012 CrossRefPubMed

Ghasemi T, Abnous K, Vahdati F, Mehri S, Razavi B, Hosseinzadeh H (2015) Antidepressant effect of Crocus Sativus aqueous extract and its effect on CREB, BDNF, and VGF transcript and protein levels in rat hippocampus. Drug research 65(07):337–343. https://doi.org/10.1055/s-0034-1371876 PubMedCrossRef

Ghoneim FM, Khalaf HA, Elsamanoudy AZ, Helaly AN (2014) Effect of chronic usage of tramadol on motor cerebral cortex and testicular tissues of adult male albino rats and the effect of its withdrawal: histological, immunohistochemical and biochemical study. Int J Clin Exp Pathol 7:7323PubMedPubMedCentral

Grond S, Sablotzki A (2004) Clinical pharmacology of tramadol. Clin Pharmacokinet 43(13):879–923. https://doi.org/10.2165/00003088-200443130-00004 CrossRefPubMed

Hara K, Minami K, Sata T (2005) The effects of tramadol and its metabolite on glycine, γ-aminobutyric AcidA, and N-methyl-d-aspartate receptors expressed in Xenopus oocytes. Anesth Analg 100(5):1400–1405. https://doi.org/10.1213/01.ANE.0000150961.24747.98 CrossRefPubMed

Hassani FV, Naseri V, Razavi BM, Mehri S, Abnous K, Hosseinzadeh H (2014) Antidepressant effects of crocin and its effects on transcript and protein levels of CREB, BDNF, and VGF in rat hippocampus. DARU Journal of Pharmaceutical Sciences 22(1):16. https://doi.org/10.1186/2008-2231-22-16 CrossRef

Hassanian-Moghaddam H, Farajidana H, Sarjami S, Owliaey H (2013) Tramadol-induced apnea. Am J Emerg Med 31(1):26–31. https://doi.org/10.1016/j.ajem.2012.05.013 CrossRefPubMed

Hiroshi K, Takaya M, Shimohama S, Kimura J, Hirano T, Gotoh Y, Nishida E (1997) Activation and involvement of p38 mitogen-activated protein kinase in glutamate-induced apoptosis in rat cerebellar granule cells. J Biol Chem 272(30):18518–18521. https://doi.org/10.1074/jbc.272.30.18518 CrossRef

Hosseini-Sharifabad A, Rabbani M, Sharifzadeh M, Bagheri N (2016) Acute and chronic tramadol administration impair spatial memory in rat. Research in pharmaceutical sciences 11:49CrossRefPubMedPubMedCentral

Hosseinzadeh H, Sadeghnia HR, Rahimi A (2008) Effect of safranal on extracellular hippocampal levels of glutamate and aspartate during kainic acid treatment in anesthetized rats. Planta Med 74(12):1441–1445. https://doi.org/10.1055/s-2008-1081335 CrossRefPubMed

Huang H, Liu C-M, Sun J, Hao T, Xu C-M, Wang D, Wu Y-Q (2016) Ketamine affects the neurogenesis of the hippocampal dentate gyrus in 7-day-old. Rats. Neurotox Res 30(2):1–14. https://doi.org/10.1007/s12640-016-9615-7 CrossRef

Jortner BS (2005) Neuropathological assessment in acute neurotoxic states. The “dark” neuron. J med CBR Def 3:1–5

Kawasaki H, Morooka T, Shimohama S, Kimura J, Hirano T, Gotoh Y, Nishida E (1997) Activation and involvement of p38 mitogen-activated protein kinase in glutamate-induced apoptosis in rat cerebellar granule cells. J Biol Chem 272:18518–18521. https://doi.org/10.1074/jbc.272.30.18518

Loughrey M, Loughrey C, Johnston S, O’Rourke D (2003) Fatal hepatic failure following accidental tramadol overdose. Forensic Sci Int 134(2-3):232–233. https://doi.org/10.1016/S0379-0738(03)00132-4 CrossRefPubMed

Manral A, Meena P, Saini V, Siraj F, Shalini S, Tiwari M (2016) DADS analogues ameliorated the cognitive impairments of Alzheimer-like rat model induced by scopolamine. Neurotox Res 30(3):1–20. https://doi.org/10.1007/s12640-016-9625-5 CrossRef

Matthiesen T, Wöhrmann T, Coogan TP, Uragg H (1998) The experimental toxicology of tramadol: an overview. Toxicol Lett 95(1):63–71. https://doi.org/10.1016/S0378-4274(98)00023-X CrossRefPubMed

Mehdizadeh H et al. (2017) Mitochondrial impairments contribute to spatial learning and memory dysfunction induced by chronic tramadol administration in rat: Protective effect of physical exercise. Prog Neuropsychopharmacol Biol Psychiatry 79:426–433. https://doi.org/10.1016/j.pnpbp.2017.07.022

McEntee WJ, Crook TH (1993) Glutamate: its role in learning, memory, and the aging brain. Psychopharmacology 111(4):391–401. https://doi.org/10.1007/BF02253527 CrossRefPubMed

Milajerdi A, Bitarafan V, Mahmoudi M (2015) A review on the effects of saffron extract and its constituents on factors related to neurologic, cardiovascular and gastrointestinal diseases. Journal of Medicinal Plants 3:9–28

Moghaddam SN, Qujeq D, Efahani AAR (2016) Effects of aqueous extract of saffron on gamma-amino butyric acid content in rat Hypothalami. Avicenna journal of medical. Biochemistry 4(In Press). https://doi.org/10.17795/ajmb.29429

Mohamed TM, Ghaffar HMA, El Husseiny RM (2015) Effects of tramadol, clonazepam, and their combination on brain mitochondrial complexes. Toxicol Ind Health 31(12):1325–1333. https://doi.org/10.1177/0748233713491814 CrossRefPubMed

Mohammadipour A, Hosseini M, Fazel A, Haghir H, Rafatpanah H, Pourganji M, Bideskan AE (2016) The effects of exposure to titanium dioxide nanoparticles during lactation period on learning and memory of rat offspring. Toxicol Ind Health 32(2):221–228. https://doi.org/10.1177/0748233713498440 CrossRefPubMed

Nakamura M, Minami K, Uezono Y, Horishita T, Ogata J, Shiraishi M, Okamoto T, Terada T, Sata T (2005) The effects of the tramadol metabolite O-desmethyl tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M1 or M3 receptors. Anesth Analg 101(1):180–186. https://doi.org/10.1213/01.ANE.0000154303.93909.A3 CrossRefPubMed

Nam KN, Park YM, Jung HJ, Lee JY, Min BD, Park SU, Jung WS, Cho KH, Park JH, Kang I, Hong JW, Lee EH (2010) Anti-inflammatory effects of crocin and crocetin in rat brain microglial cells. Eur J Pharmacol 648(1-3):110–116. https://doi.org/10.1016/j.ejphar.2010.09.003 CrossRefPubMed

Papandreou MA, Tsachaki M, Efthimiopoulos S, Cordopatis P, Lamari FN, Margarity M (2011) Memory enhancing effects of saffron in aged mice are correlated with antioxidant protection. Behav Brain Res 219(2):197–204. https://doi.org/10.1016/j.bbr.2011.01.007 CrossRefPubMed

Pitsikas N, Boultadakis A, Georgiadou G, Tarantilis P, Sakellaridis N (2008) Effects of the active constituents of Crocus Sativus L., crocins, in an animal model of anxiety. Phytomedicine 15(12):1135–1139. https://doi.org/10.1016/j.phymed.2008.06.005 CrossRefPubMed

Purushothuman S, Nandasena C, Peoples CL, El Massri N, Johnstone DM, Mitrofanis J, Stone J (2013) Saffron pre-treatment offers neuroprotection to Nigral and retinal dopaminergic cells of MPTP-treated mice. Journal of Parkinson's disease 3:77–83. https://doi.org/10.3233/JPD-130173 PubMedCrossRef

Rehni AK, Singh I, Kumar M (2008) Tramadol-induced Seizurogenic effect: a possible role of opioid-dependent γ-aminobutyric acid inhibitory pathway. Basic & clinical pharmacology & toxicology 103(3):262–266. https://doi.org/10.1111/j.1742-7843.2008.00276.x CrossRef

Sadeghi A, Bideskan AE, Alipour F, Fazel A, Haghir H (2013) The effect of ascorbic acid and garlic administration on lead-induced neural damage in rat offspring’s hippocampus. Iranian journal of basic medical sciences 16:157PubMedPubMedCentral

Sadeghnia HR, Kamkar M, Assadpour E, Boroushaki MT, Ghorbani A (2013) Protective effect of safranal, a constituent of Crocus Sativus, on quinolinic acid-induced oxidative damage in rat hippocampus. Iranian journal of basic medical sciences 16:73–82. https://doi.org/10.22038/ijbms.2013.251 PubMedPubMedCentralCrossRef

Samarghandian S, Azimi-Nezhad M, Samini F (2014) Ameliorative effect of saffron aqueous extract on hyperglycemia, hyperlipidemia, and oxidative stress on diabetic encephalopathy in streptozotocin induced experimental diabetes mellitus. Biomed Res Int 2014:1–12. https://doi.org/10.1155/2014/920857 CrossRef

Shah N, Thomas E, Jose R, Peedicayil J (2013) Tramadol inhibits the contractility of isolated human myometrium. Autonomic and Autacoid Pharmacology 33(1-2):1–5. https://doi.org/10.1111/aap.12003 CrossRefPubMed

Tamaddonfard E, Farshid AA, Asri-Rezaee S, Javadi S, Khosravi V, Rahman B, Mirfakhraee Z (2013) Crocin improved learning and memory impairments in streptozotocin-induced diabetic rats. Iranian journal of basic medical sciences 16:91-100. https://doi.org/10.22038/ijbms.2013.253

Yan T, Huan X, Wei J, Yun-cheng N, Wei-feng Q, Peng-cheng W (2011) Effect of tramadol with different doses on the learning and memory of mice. Journal of Jinggangshan University (Natural Science) 3:28

Zeng L-H, Ouyang Y, Gazit V, Cirrito JR, Jansen LA, Ess KC, Yamada KA, Wozniak DF, Holtzman DM, Gutmann DH, Wong M (2007) Abnormal glutamate homeostasis and impaired synaptic plasticity and learning in a mouse model of tuberous sclerosis complex. Neurobiol Dis 28(2):184–196. https://doi.org/10.1016/j.nbd.2007.07.015 CrossRefPubMedPubMedCentral

Zhuo H-Q, Huang L, Huang H-Q, Cai Z (2012) Effects of chronic tramadol exposure on the zebrafish brain: a proteomic study. J Proteome 75(11):3351–3364. https://doi.org/10.1016/j.jprot.2012.03.038 CrossRef

Title: The effects of tramadol administration on hippocampal cell apoptosis, learning and memory in adult rats and neuroprotective effects of crocin
Authors: Farideh Baghishani
Abbas Mohammadipour
Hossain Hosseinzadeh
Mahmoud Hosseini
Alireza Ebrahimzadeh-bideskan
Publication date: 01-06-2018
Publisher: Springer US
Published in: Metabolic Brain Disease / Issue 3/2018
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-018-0194-6

At a glance: The STEP trials

Springer Medicine

The effects of tramadol administration on hippocampal cell apoptosis, learning and memory in adult rats and neuroprotective effects of crocin

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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