Drug Res (Stuttg) 2019; 69(06): 323-329
DOI: 10.1055/a-0790-8200
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Safranal Attenuates Excitotoxin-Induced Oxidative OLN-93 Cells Injury

Mohaddeseh Sadat Alavi
1   Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
3   Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
,
Sahar Fanoudi
2   Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
3   Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
,
Ameneh Veisi Fard
3   Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
,
Mohammad Soukhtanloo
4   Department of Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
,
Mahmoud Hosseini
2   Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
,
Hanif Barzegar
3   Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
,
Hamid R. Sadeghnia
1   Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
2   Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
3   Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Publikationsverlauf

received 04. Juli 2018

accepted 06. November 2018

Publikationsdatum:
21. November 2018 (online)

Abstract

Objectives Researches have been shown that glutamic acid (GA) or quinolinic acid (QA) can play role in neuroinflammatory and demyelinating diseases including multiple sclerosis (MS), mainly via oligodendrocytes activation and extreme free radicals generation. Recent studies have demonstrated that safranal, an active constituent of Crocus sativus, has several pharmacological effects such as antioxidant, anti-inflammatory and neuroprotective properties. Since there is no data about the impact of safranal on MS, this study was designed to investigate the protective effect of safranal on OLN-93 oligodendrocytes injury induced by GA or QA.

Materials and Methods At first, the potential toxic effect of safranal on OLN-93 viability was evaluated. Also, the cells were pretreated with safranal (0.1, 1, 10, 50, 100 and 200 μM) for 2 h and then subjected to GA (16 mM) or QA (8 mM) toxicity for 24 h, in which the same treatments were applied. The cell viability and parameters of redox status such as the levels of intracellular reactive oxygen species (ROS) and lipid peroxidation were measured.

Results Safranal at concentration ranges of 1–800 μM had no toxic effect on cell viability (p>0.05). Treatment with safranal significantly increased cell viability following GA or QA insults at concentrations higher than 1 μM (p<0.01). The cytoprotective potential of safranal was also accompanied by decreased ROS accumulation (p<0.001) and malondialdehyde level (p<0.001) following GA or QA insults.

Conclusion The data suggests that safranal exhibits oligoprotection potential by means of inhibiting oxidative stress parameters.

* These 2 authors contributed equally to this work.


 
  • References

  • 1 Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch 2010; 460: 525-542
  • 2 Kolobov V, Davydova T, Zakharova I. et al. Glutamate antibodies repress expression of Dffb gene in brain of rats in experimental Alzheimer’s disease. Molecular Biology 2012; 46: 678-686
  • 3 Saab AS, Tzvetavona ID, Trevisiol A. et al. Nligodendroglial NMDA receptors regulate glucose import and axonal energy metabolism. Neuron 2016; 91: 119-132
  • 4 Karadottir R, Cavelier P, Bergersen LH. et al. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature 2005; 438: 1162-1166
  • 5 Bercury KK, Macklin WB. Dynamics and mechanisms of CNS myelination. Dev Cell 2015; 32: 447-458
  • 6 Guillemin GJ, Brew BJ. Implications of the kynurenine pathway and quinolinic acid in Alzheimer's disease. Redox Report 2002; 7: 199-206
  • 7 Guillemin GJ. Quinolinic acid, the inescapable neurotoxin. FEBS J 2012; 279: 1356-1365
  • 8 Carson MJ, Thrash JC, Walter B. The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival. Clin Neurosci Res 2006; 6: 237-245
  • 9 Zadori D, Klivenyi P, Vamos E. et al. Kynurenines in chronic neurodegenerative disorders: future therapeutic strategies. J Neural Transm (Vienna) 2009; 116: 1403-1409
  • 10 Chen Y, Guillemin GJ. Kynurenine pathway metabolites in humans: disease and healthy States. Int J Tryptophan Res 2009; 2: 1-19
  • 11 Perez-De La Cruz V, Carrillo-Mora P, Santamaria A. Quinolinic acid, an endogenous molecule combining excitotoxicity, oxidative stress and other toxic mechanisms. Int J Tryptophan Res 2012; 5: 1-8
  • 12 Sundaram G, Brew BJ, Jones SP. et al. Quinolinic acid toxicity on oligodendroglial cells: relevance for multiple sclerosis and therapeutic strategies. J Neuroinflammation 2014; 11: 204
  • 13 Wu PF, Zhang Z, Wang F. et al. Natural compounds from traditional medicinal herbs in the treatment of cerebral ischemia/reperfusion injury. Acta Pharmacol Sin 2010; 31: 1523-1531
  • 14 Rameshrad M, Razavi BM, Hosseinzadeh H. Saffron and its derivatives, crocin, crocetin and safranal: a patent review. Expert Opin Ther Pat 2017
  • 15 Tarantilis PA, Tsoupras G, Polissiou M. Determination of saffron (Crocus sativus L.) components in crude plant extract using high-performance liquid chromatography-UV-visible photodiode-array detection-mass spectrometry. J Chromatogr A 1995; 699: 107-118
  • 16 Sadeghnia HR, Shaterzadeh H, Forouzanfar F. et al. Neuroprotective effect of safranal, an active ingredient of Crocus sativus, in a rat model of transient cerebral ischemia. Folia Neuropathol 2017; 55: 206-213
  • 17 Assimopoulou AN, Sinakos Z, Papageorgiou VP. Radical scavenging activity of Crocus sativus L. extract and its bioactive constituents. Phytother Res 2005; 19: 997-1000
  • 18 Hosseinzadeh H, Noraei NB. Anxiolytic and hypnotic effect of Crocus sativus aqueous extract and its constituents, crocin and safranal, in mice. Phytother Res 2009; 23: 768-774
  • 19 Amin B, Hosseinzadeh H. Evaluation of aqueous and ethanolic extracts of saffron, Crocus sativus L., and its constituents, safranal and crocin in allodynia and hyperalgesia induced by chronic constriction injury model of neuropathic pain in rats. Fitoterapia 2012; 83: 888-895
  • 20 Hosseinzadeh H, Sadeghnia HR. Protective effect of safranal on pentylenetetrazol-induced seizures in the rat: involvement of GABAergic and opioids systems. Phytomedicine 2007; 14: 256-262
  • 21 Moshiri M, Vahabzadeh M, Hosseinzadeh H. Clinical applications of saffron (Crocus sativus) and its constituents: A review. Drug Res (Stuttg) 2015; 65: 287-295
  • 22 Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55-63
  • 23 Sadeghnia HR, Jamshidi R, Afshari AR. et al. Terminalia chebula attenuates quinolinate-induced oxidative PC12 and OLN-93 cell death. Mult Scler Relat Disord 2017; 14: 60-67
  • 24 Rajabian A, Boroushaki MT, Hayatdavoudi P. et al. Boswellia serrata protects against glutamate-induced oxidative stress and apoptosis in PC12 and N2a cells. DNA Cell Biol 2016; 35: 666-679
  • 25 Hu S, Cui W, Mak S. et al. Bis(propyl)-cognitin protects against glutamate-induced neuro-excitotoxicity via concurrent regulation of NO, MAPK/ERK and PI3-K/Akt/GSK3beta pathways. Neurochem Int 2013; 62: 468-477
  • 26 Kim EK, Lee SJ, Moon SH. et al. Neuroprotective effects of a novel peptide purified from venison protein. J Microbiol Biotechnol 2010; 20: 700-707
  • 27 LeBel CP, Ali SF, McKee M. et al. Organometal-induced increases in oxygen reactive species: the potential of 2',7'-dichlorofluorescin diacetate as an index of neurotoxic damage. Toxicol Appl Pharmacol 1990; 104: 17-24
  • 28 Wallack EM, Wiseman HD, Ploughman M. Healthy aging from the perspectives of 683 older people with multiple sclerosis. Mult Scler Int 2016; 2016: 1845720
  • 29 Lassmann H, van Horssen J. Oxidative stress and its impact on neurons and glia in multiple sclerosis lesions. Biochim Biophys Acta 2016; 1862: 506-510
  • 30 Richter-Landsberg C, Heinrich M. OLN-93: a new permanent oligodendroglia cell line derived from primary rat brain glial cultures. J Neurosci Res 1996; 45: 161-173
  • 31 Kolodziejczyk K, Saab AS, Nave KA. et al. Why do oligodendrocyte lineage cells express glutamate receptors?. F1000 Biol Rep 2010; 2: 57
  • 32 Hernandez-Martinez JM, Forrest CM, Darlington LG. et al. Quinolinic acid induces neuritogenesis in SH-SY5Y neuroblastoma cells independently of NMDA receptor activation. Eur J Neurosci 2017; 45: 700-711
  • 33 Matute C. Oligodendrocyte NMDA receptors: a novel therapeutic target. Trends Mol Med 2006; 12: 289-292
  • 34 Dong XX, Wang Y, Qin ZH. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sin 2009; 30: 379-387
  • 35 Li H, Han W, Wang H. et al. Tanshinone IIa inhibits glutamate-induced oxidative toxicity through prevention of mitochondrial dysfunction and suppression of mapk activation in SH-SY5Y human neuroblastoma cells. Oxid Med Cell Longev 2017; 2017: 4517486
  • 36 Penugonda S, Mare S, Goldstein G. et al. Effects of N-acetylcysteine amide (NACA), a novel thiol antioxidant against glutamate-induced cytotoxicity in neuronal cell line PC12. Brain Res 2005; 1056: 132-138
  • 37 Salter MG, Fern R. NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature 2005; 438: 1167-1171
  • 38 Azevedo CJ, Kornak J, Chu P. et al. In vivo evidence of glutamate toxicity in multiple sclerosis. Ann Neurol 2014; 76: 269-278
  • 39 Cabrera J, Reiter RJ, Tan DX. et al. Melatonin reduces oxidative neurotoxicity due to quinolinic acid: in vitro and in vivo findings. Neuropharmacology 2000; 39: 507-514
  • 40 Oboh G, Rocha JB. Hot Pepper (Capsicum spp.) protects brain from sodium nitroprusside- and quinolinic acid-induced oxidative stress in vitro. J Med Food 2008; 11: 349-355
  • 41 Muller AC, Maharaj H, Maharaj DS. et al. Aciclovir protects against quinolinic-acid-induced oxidative neurotoxicity. J Pharm Pharmacol 2005; 57: 883-888
  • 42 Sas K, Robotka H, Toldi J. et al. Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders. J Neurol Sci 2007; 257: 221-239
  • 43 Tavares RG, Tasca CI, Santos CE. et al. Quinolinic acid stimulates synaptosomal glutamate release and inhibits glutamate uptake into astrocytes. Neurochem Int 2002; 40: 621-627
  • 44 Wu HQ, Lee SC, Schwarcz R. Systemic administration of 4-chlorokynurenine prevents quinolinate neurotoxicity in the rat hippocampus. Eur J Pharmacol 2000; 390: 267-274
  • 45 Lee HH, Yang LL, Wang CC. et al. Differential effects of natural polyphenols on neuronal survival in primary cultured central neurons against glutamate- and glucose deprivation-induced neuronal death. Brain Res 2003; 986: 103-113
  • 46 Sadeghnia HR, Kamkar M, Assadpour E. et al. Protective effect of safranal, a constituent of Crocus sativus, on quinolinic acid-induced oxidative damage in rat hippocampus. Iran J Basic Med Sci 2013; 16: 73-82
  • 47 Feyzi R, Boskabady MH, Seyedhosseini Tamijani SM. et al. The Effect of safranal on Th1/Th2 cytokine balance. Iran J Immunol 2016; 13: 263-273
  • 48 Zhang C, Ma J, Fan L. et al. Neuroprotective effects of safranal in a rat model of traumatic injury to the spinal cord by anti-apoptotic, anti-inflammatory and edema-attenuating. Tissue Cell 2015; 47: 291-300
  • 49 Samarghandian S, Borji A. Anticarcinogenic effect of saffron (Crocus sativus L.) and its ingredients. Pharmacognosy Res 2014; 6: 99-107
  • 50 Khazdair MR, Boskabady MH, Hosseini M. et al. The effects of Crocus sativus (saffron) and its constituents on nervous system: A review. Avicenna J Phytomed 2015; 5: 376-391
  • 51 Hosseinzadeh H, Sadeghnia HR. Safranal, a constituent of Crocus sativus (saffron), attenuated cerebral ischemia induced oxidative damage in rat hippocampus. J Pharm Pharm Sci 2005; 8: 394-399
  • 52 Bukhari SI, Pattnaik B, Rayees S. et al. Safranal of Crocus sativus L. inhibits inducible nitric oxide synthase and attenuates asthma in a mouse model of asthma. Phytother Res 2015; 29: 617-627
  • 53 Pan P, Qiao L, Wen X. Safranal prevents rotenone-induced oxidative stress and apoptosis in an in vitro model of Parkinson's disease through regulating Keap1/Nrf2 signaling pathway. Cell Mol Biol (Noisy-le-Grand) 2016; 62: 11-17
  • 54 Farshid AA, Tamaddonfard E. Histopathological and behavioral evaluations of the effects of crocin, safranal and insulin on diabetic peripheral neuropathy in rats. Avicenna J Phytomed 2015; 5: 469-478
  • 55 Delkhosh-Kasmaie F, Farshid AA, Tamaddonfard E. et al. The effects of safranal, a constitute of saffron, and metformin on spatial learning and memory impairments in type-1 diabetic rats: behavioral and hippocampal histopathological and biochemical evaluations. Biomed Pharmacother 2018; 107: 203-211
  • 56 Hosseinzadeh H, Modaghegh MH, Saffari Z. Crocus sativus L. (Saffron) extract and its active constituents (crocin and safranal) on ischemia-reperfusion in rat skeletal muscle. Evid Based Complement Alternat Med 2009; 6: 343-350
  • 57 Hosseinzadeh H, Sadeghnia HR, Rahimi A. Effect of safranal on extracellular hippocampal levels of glutamate and aspartate during kainic acid treatment in anesthetized rats. Planta Med 2008; 74: 1441-1445
  • 58 Tamaddonfard E, Farshid AA, Eghdami K. et al. Comparison of the effects of crocin, safranal and diclofenac on local inflammation and inflammatory pain responses induced by carrageenan in rats. Pharmacol Rep 2013; 65: 1272-1280