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Nutritional Neuroscience
An International Journal on Nutrition, Diet and Nervous System
Volume 23, 2020 - Issue 3
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Articles

Crocin-protected malathion-induced spatial memory deficits by inhibiting TAU protein hyperphosphorylation and antiapoptotic effects

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References

  • Howes MJR, Perry NS, Houghton PJ. Plants with traditional uses and activities, relevant to the management of Alzheimer’s disease and other cognitive disorders. Phytother Res 2003;17(1):1–18.
  • Pooler AM, Noble W, Hanger DP. A role for tau at the synapse in Alzheimer’s disease pathogenesis. Neuropharmacology 2014;76:1–8.
  • Morris M, Maeda S, Vossel K, Mucke L. The many faces of tau. Neuron 2011;70(3):410–26.
  • Parrón T, Requena M, Hernández AF, Alarcón R. Association between environmental exposure to pesticides and neurodegenerative diseases. Toxicol Appl Pharmacol 2011;256(3):379–85.
  • Assini FL, Zanette KD, Brocardo PS, Pandolfo P, Rodrigues ALS, Takahashi RN. Behavioral effects and ChE measures after acute and repeated administration of malathion in rats. Environ Toxicol Pharmacol 2005;20(3):443–9.
  • Hariri AT, Moallem SA, Mahmoudi M, Hosseinzadeh H. The effect of crocin and safranal, constituents of saffron, against subacute effect of diazinon on hematological and genotoxicity indices in rats. Phytomedicine 2011;18(6):499–504.
  • Sargazi Z, Nikravesh MR, Jalali M, Sadeghnia H, Anbarkeh FR, Mohammadzadeh L. Gender-related differences in sensitivity to diazinon in gonads of adult rats and the protective effect of vitamin E. IJWHR 2015;3(1):40–7.
  • Brocardo PS, Pandolfo P, Takahashi RN, Rodrigues ALS, Dafre AL. Antioxidant defenses and lipid peroxidation in the cerebral cortex and hippocampus following acute exposure to malathion and/or zinc chloride. Toxicology 2005;207(2):283–91.
  • Middlemore-Risher M-L, Buccafusco J, Terry AV. Repeated exposures to low-level chlorpyrifos results in impairments in sustained attention and increased impulsivity in rats. Neurotoxicol Teratol 2010;32(4):415–24.
  • Yadav SS, Singh MK, Yadav RS. Organophosphates induced Alzheimer’s disease: an epigenetic aspect. J Clin Epigenet 2016;2:1. DOI:10.21767/2472-1158.100010.
  • G. Salazar J, Ribes D, Cabre ML, L. Domingo J, Sanchez-Santed F, Teresa Colomina M. Amyloid β peptide levels increase in brain of AβPP Swedish mice after exposure to chlorpyrifos. Curr Alzheimer Res 2011;8(7):732–40.
  • Campaña AD, Sanchez F, Gamboa C, Gómez-Villalobos MDJ, De La Cruz F, Zamudio S, et al. Dendritic morphology on neurons from prefrontal cortex, hippocampus, and nucleus accumbens is altered in adult male mice exposed to repeated low dose of malathion. Synapse 2008;62(4):283–90.
  • Abdollahi M, Ranjbar A, Shadnia S, Nikfar S, Rezaiee A. Pesticides and oxidative stress: a review. Med Sci Monit 2004;10(6):RA141–RA7.
  • Ahmed T, Tripathi A, Suke S, Kumar V, Ahmed R, Das S, et al. Role of HSP27 and reduced glutathione in modulating malathion-induced apoptosis of human peripheral blood mononuclear cells: ameliorating effect of N-acetylcysteine and curcumin. Toxicol In Vitro 2009;23:1319–25.
  • Masoud L, Vijayasarathy C, Fernandez-Cabezudo M, Petroianu G, Saleh A. Effect of malathion on apoptosis of murine L929 fibroblasts: a possible mechanism for toxicity in low dose exposure. Toxicology 2003;185(1):89–102.
  • Rohn TT, Rissman RA, Davis MC, Kim YE, Cotman CW, Head E. Caspase-9 activation and caspase cleavage of tau in the Alzheimer’s disease brain. Neurobiol Dis 2002;11(2):341–54.
  • Terry A. Functional consequences of repeated organophosphate exposure: potential Non-cholinergic mechanisms. Pharmacol Ther 2012;134:355–65.
  • Alavizadeh SH, Hosseinzadeh H. Bioactivity assessment and toxicity of crocin: a comprehensive review. Food Chem Toxicol 2014;64:65–80.
  • Mollazadeh H, Emami SA, Hosseinzadeh H. Razi’s Al-Hawi and saffron (Crocus sativus): a review. Iran J Basic Med Sci 2015;18(12):1153.
  • Fernández J-A. Anticancer properties of saffron, Crocus sativus Linn. Advances in Phytomedicine 2006;2:313–30.
  • Hosseinzadeh H, Shamsaie F, Mehri S. Antioxidant activity of aqueous and ethanolic extracts of Crocus sativus L. stigma and its bioactive constituents, crocin and safranal. Pharmacogn Mag 2009;5(20):419.
  • Assimopoulou A, Sinakos Z, Papageorgiou V. Radical scavenging activity of Crocus sativus L. extract and its bioactive constituents. Phytother Res 2005;19(11):997–1000.
  • Hosseinzadeh H, Younesi HM. Antinociceptive and anti-inflammatory effects of Crocus sativus L. stigma and petal extracts in mice. BMC Pharmacol 2002;2(1):1–8.
  • Khosravan V. Anticonvulsant effects of aqueous and ethanolic extracts of Crocus sativus L. stigmas in mice. Arc Iran Medi 2002;5:44.
  • Razavi BM, Hosseinzadeh H. Saffron: a promising natural medicine in the treatment of metabolic syndrome. J Sci Food Agric 2017;97:1679–85.
  • Khorasany AR, Hosseinzadeh H. Therapeutic effects of saffron (Crocus sativus L.) in digestive disorders: a review. Iran J Basic Med Sci 2016;19(5):455.
  • Hosseinzadeh H, Ziaei T. Effects of Crocus sativus stigma extract and its constituents, crocin and safranal, on intact memory and scopolamine-induced learning deficits in rats performing the Morris water maze task. J Med Plants 2006;3(19):40–50.
  • Soeda S, Ochiai T, Shimeno H, Saito H, Abe K, Tanaka H, et al. Pharmacological activities of crocin in saffron. J Nat Med 2007;61(2):102–11.
  • 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(3):343–50.
  • Hosseinzadeh H, Sadeghnia H. Safranal, a constituent of Crocus sativus (saffron), attenuated cerebral ischemia induced oxidative damage in rat hippocampus. J Pharm Pharm Sci 2005;8:394–9.
  • Razavi BM, Hosseinzadeh H, Movassaghi AR, Imenshahidi M, Abnous K. Protective effect of crocin on diazinon induced cardiotoxicity in rats in subchronic exposure. Chem Biol Interact 2013;203(3):547–55.
  • Mehri S, Abnous K, Mousavi SH, Shariaty VM, Hosseinzadeh H. Neuroprotective effect of crocin on acrylamide-induced cytotoxicity in PC12 cells. Cell Mol Neurobiol 2012;32(2):227–35.
  • Dorri SA, Hosseinzadeh H, Abnous K, Hasani FV, Robati RY, Razavi BM. Involvement of brain-derived neurotrophic factor (BDNF) on malathion induced depressive-like behavior in subacute exposure and protective effects of crocin. Iran J Basic Med Sci 2015;18(10):958.
  • Hosseinzadeh H, Sadeghnia HR, Ghaeni FA, Motamedshariaty VS, Mohajeri SA. Effects of saffron (Crocus sativus L.) and its active constituent, crocin, on recognition and spatial memory after chronic cerebral hypoperfusion in rats. Phytother Res 2012;26(3):381–6.
  • Papandreou MA, Kanakis CD, Polissiou MG, Efthimiopoulos S, Cordopatis P, Margarity M, et al. Inhibitory activity on amyloid-β aggregation and antioxidant properties of Crocus sativus stigmas extract and its crocin constituents. J Agric Food Chem 2006;54(23):8762–8.
  • Khalili M, Roghani M, Ekhlasi M. The effect of aqueous crocus sativus L. extract on intracerebroventricular streptozotocin-induced cognitive deficits in rat: a behavioral analysis. Iran J Pharm Res 2010;8:185–91.
  • Hadizadeh F, Mohajeri S, Seifi M. Extraction and purification of crocin from saffron stigmas employing a simple and efficient crystallization method. Pak J Biol Sci 2010;13(14):691–8.
  • Delgado EH, Streck EL, Quevedo JL, Dal-Pizzol F. Mitochondrial respiratory dysfunction and oxidative stress after chronic malathion exposure. Neurochem Res 2006;31(8):1021–5.
  • Wass C, Archer T, Palsson E, Fejgin K, Klamer D, Engel JA, et al. Protective effects of effects of phencyclidine on spatial learning and memory: nitric oxide-dependent mechanisms. Behav Brain Res 2006;171:147–53.
  • Henderson A. The risk factors for Alzheimer’s disease: a review and a hypothesis. Acta Psychiatr Scand 1988;78(3):257–75.
  • Vorhees CV, Williams MT. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nature Protocols 2006;1(2):848–58.
  • Rezg R, Mornagui B, El-Fazaa S, Gharbi N. Biochemical evaluation of hepatic damage in subchronic exposure to malathion in rats: effect on superoxide dismutase and catalase activities using native PAGE. Comptes Rendus Biologies 2008;331(9):655–62.
  • Gorun V, Proinov I, Băltescu V, Balaban G, Bârzu O. Modified Ellman procedure for assay of cholinesterases in crude enzymatic preparations. Anal Biochem 1978;86(1):324–6.
  • Fernández J, Pérez-Álvarez JA, Fernández-López JA. Thiobarbituric acid test for monitoring lipid oxidation in meat. Food Chem 1997;59(3):345–3.
  • Moron MS, Depierre JW, Mannervik B. Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. BBA-Gen Sub 1979;582(1):67–78.
  • Ye S-M, Johnson RW. Increased interleukin-6 expression by microglia from brain of aged mice. J Neuroimmunol 1999;93(1):139–48.
  • Özdemir HH, Kara M, Yumrutas O, Uckardes F, Eraslan E, Demir CF, et al. Determination of the effects on learning and memory performance and related gene expressions of clothianidin in rat models. Cogn Neurodyn 2014;8(5):411–16.
  • Sanchez-Santed F, Colomina MT, Hernández EH. Organophosphate pesticide exposure and neurodegeneration. Cortex 2016;74:417–26.
  • Yan C, Jiao L, Zhao J, Yang H, Peng S. Repeated exposures to chlorpyrifos lead to spatial memory retrieval impairment and motor activity alteration. Neurotoxicol Teratol 2012;34(4):442–9.
  • Pitsikas N, Zisopoulou S, Tarantilis PA, Kanakis CD, Polissiou MG, Sakellaridis N. Effects of the active constituents of Crocus sativus L., crocins on recognition and spatial rats’ memory. Behav Brain Res 2007;183(2):141–6.
  • Dos Santos AA, Naime AA, de Oliveira J, Colle D, Dos Santos DB, Hort MA, et al. Long-term and low-dose malathion exposure causes cognitive impairment in adult mice: evidence of hippocampal mitochondrial dysfunction, astrogliosis and apoptotic events. Arch Toxicol 2016;90(3):647–60.
  • Castillo C, Montante M, Dufour L, Martınez M, Jiménez-Capdeville M. Behavioral effects of exposure to endosulfan and methyl parathion in adult rats. Neurotoxicol Teratol 2002;24(6):797–804.
  • Chen N-N, Luo D-J, Yao X-Q, Yu C, Wang Y, Wang Q, et al. Pesticides induce spatial memory deficits with synaptic impairments and an imbalanced tau phosphorylation in rats. J Alzheimers Dis 2012;30(3):585–94.
  • Ghadrdoost B, Vafaei AA, Rashidy-Pour A, Hajisoltani R, Bandegi AR, Motamedi F, et al. 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 2011;667(1):222–9.
  • Zafar KS, Siddiqui A, Sayeed I, Ahmad M, Saleem S, Islam F. Protective effect of adenosine in rat model of Parkinson’s disease: neurobehavioral and neurochemical evidences. J Chem Neuroanat 2003;26(2):143–51.
  • Abdollahi m, Mostafalou S, Pournourmohammadi S, Shadnia S. Oxidative stress and cholinesterase inhibition in saliva and plasma of rats following subchronic exposure to malathion. Comp Biochem Physiol C Toxicol Pharmacol 2004;137(1):29–34.
  • Lovell MA, Ehmann WD, Butler SM, Markesbery WR. Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer’s disease. Neurology 1995;45(8):1594–601.
  • Abdel-Daim MM. Synergistic protective role of ceftriaxone and ascorbic acid against subacute diazinon-induced nephrotoxicity in rats. Cytotechnology 2016;68(2):279–89.
  • Abdel-Daim MM, Taha R, Ghazy EW, El-Sayed YS. Synergistic ameliorative effects of sesame oil and alpha-lipoic acid against subacute diazinon toxicity in rats: hematological, biochemical, and antioxidant studies. Canad J Physiol Pharm 2016;94(1):81–8.
  • Abdelkhalek NK, Eissa IA, Ahmed E, Kilany OE, El-Adl M, Dawood MA, et al. Protective role of dietary Spirulina platensis against diazinon-induced oxidative damage in Nile tilapia; oreochromis niloticus. Environ Toxicol Pharmacol 2017;54:99–104.
  • Ogutcu A, Uzunhisarcikli M, Kalender S, Durak D, Bayrakdar F, Kalender Y. The effects of organophosphate insecticide diazinon on malondialdehyde levels and myocardial cells in rat heart tissue and protective role of vitamin E. Pestic Biochem Physiol 2006;86(2):93–8.
  • Mohammadzadeh L, Hosseinzadeh H, Abnous K, Razavi BM. Neuroprotective potential of crocin against malathion-induced motor deficit and neurochemical alterations in rats. Environ Sci Pollut Res 2018;25:4904–14.
  • Eghbaliferiz S, Iranshahi M. Prooxidant activity of polyphenols, flavonoids, anthocyanins and carotenoids: updated review of mechanisms and catalyzing metals. Phytother Res 2016;30(9):1379–91.
  • Grammas P, Ovase R. Inflammatory factors are elevated in brain microvessels in Alzheimer’s disease. Neurobiol Aging 2001;22(6):837–42.
  • Wenk G, McGann K, Hauss-Wegrzyniak B, Rosi S. The toxicity of tumor necrosis factor-α upon cholinergic neurons within the nucleus basalis and the role of norepinephrine in the regulation of inflammation: implications for Alzheimer’s disease. Neuroscience 2003;121(3):719–29.
  • Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging 2000;21(3):383–421.
  • Quintanilla RA, Orellana DI, González-Billault C, Maccioni RB. Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway. Exp Cell Res 2004;295(1):245–57.
  • Hariri AT, Moallem SA, Mahmoudi M, Memar B, Hosseinzadeh H. Sub-acute effects of diazinon on biochemical indices and specific biomarkers in rats: protective effects of crocin and safranal. Food Chem Toxicol 2010;48(10):2803–8.
  • Tan M-S, Yu J-T, Jiang T, Zhu X-C, Tan L. The NLRP3 inflammasome in Alzheimer’s disease. Mol Neurobiol 2013;48(3):875–82.
  • El-Beshbishy HA, Hassan MH, Aly HA, Doghish AS, Alghaithy AA. Crocin ‘saffron’ protects against beryllium chloride toxicity in rats through diminution of oxidative stress and enhancing gene expression of antioxidant enzymes. Ecotoxicol Environ Saf 2012;83:47–54.
  • Nam KN, Park Y-M, Jung H-J, Lee JY, Min BD, Park S-U, et al. Anti-inflammatory effects of crocin and crocetin in rat brain microglial cells. Eur J Pharmacol 2010;648(1):110–16.
  • Kawabata K, Tung NH, Shoyama Y, Sugie S, Mori T, Tanaka T. Dietary crocin inhibits colitis and colitis-associated colorectal carcinogenesis in male ICR mice. Evid Based Complement Alternat Med 2012;2012:1–13.
  • Halliday G, Robinson SR, Shepherd C, Kril J. Alzheimer’s disease and inflammation: a review of cellular and therapeutic mechanisms. Clin Exp Pharmacol Physiol 2000;27(1–2):1–8.
  • Lim GP, Yang F, Chu T, Chen P, Beech W, Teter B, et al. Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J Neurosci 2000;20(15):5709–14.
  • Carlisle HJ, Fink AE, Grant SGN, O’Dell TJ. Opposing effects of PSD-93 and PSD-95 on long-term potentiation and spike timing-dependent plasticity. J Physiol 2008;586:5885–5900.
  • Abe K, Saito H. Effects of saffron extract and its constituent crocin on learning behaviour and long-term potentiation. Phytother Res 2000;14(3):149–52.
  • Hadipour M, Kaka G, Bahrami F, Meftahi GH, Pirzad Jahromi G, Mohammadi A, et al. Crocin improved amyloid beta induced long-term potentiation and memory deficits in the hippocampal CA1 neurons in freely moving rats. Synapse 2018;72(5):e22026.
  • Ávila J, Lim F, Moreno F, Belmonte C, Cuello AC. Tau function and dysfunction in neurons. Mol Neurobiol 2002;25(3):213–31.
  • Wang Y, Yang R, Gu J, Yin X, Jin N, Xie S, et al. Cross talk between PI3K-AKT-GSK-3β and PP2A pathways determines tau hyperphosphorylation. Neurobio Aging 2015;36(1):188–200.
  • Crews L, Masliah E. Molecular mechanisms of neurodegeneration in Alzheimer’s disease. Hum Mol Gen 2010;19(R1):R12–R20.
  • Medina M, Avila J. Understanding the relationship between GSK-3 and Alzheimer’s disease: a focus on how GSK-3 can modulate synaptic plasticity processes. Expert Rev Neurother 2013;13(5):495–503.
  • Planel E, Yasutake K, Fujita SC, Ishiguro K. Inhibition of protein phosphatase 2A overrides tau protein kinase I/glycogen synthase kinase 3β and cyclin-dependent kinase 5 inhibition and results in tau hyperphosphorylation in the hippocampus of starved mouse. J Biol Chem 2001;276(36):34298–306.
  • Qian W, Shi J, Yin X, Iqbal K, Grundke-Iqbal I, Gong C-X, et al. Pp2a regulates tau phosphorylation directly and also indirectly via activating GSK-3β. J Alzheimers Dis 2010;19(4):1221–9.
  • Yao X-Q, Zhang X-X, Yin Y-Y, Liu B, Luo D-J, Liu D, et al. Glycogen synthase kinase-3β regulates Tyr307 phosphorylation of protein phosphatase-2A via protein tyrosine phosphatase 1B but not Src. Biochem J 2011;437(2):335–44.
  • Liu R, Zhou XW, Tanila H, Bjorkdahl C, Wang JZ, Guan ZZ, et al. Phosphorylated PP2A (tyrosine 307) is associated with Alzheimer neurofibrillary pathology. J Cell Mol Med 2008;12(1):241–57.
  • Schneider A, Mandelkow E. Tau-based treatment strategies in neurodegenerative diseases. Neurotherapeutics 2008;5(3):443–57.
  • Luo Y, Nie Y-J, Shi H-R, Ni Z-F, Wang Q, Wang J-Z, et al. Ptpa activates protein phosphatase-2A through reducing its phosphorylation at tyrosine-307 with upregulation of protein tyrosine phosphatase 1B. BBA-Mol Cell Res 2013;1833(5):1235–43.
  • Sontag J-M, Sontag E. Protein phosphatase 2A dysfunction in Alzheimer’s disease. Frontiers in Mol Neurosci 2014;7:16.
  • Zeng K-W, Ko H, Yang HO, Wang X-M. Icariin attenuates β-amyloid-induced neurotoxicity by inhibition of tau protein hyperphosphorylation in PC12 cells. Neuropharmacology 2010;59(6):542–50.
  • Rashedinia M, Lari P, Abnous K, Hosseinzadeh H. Protective effect of crocin on acrolein-induced tau phosphorylation in the rat brain. Acta Neurobiol Exp 2015;75:208–19.
  • Ashkenazi A, Dixit VM. Apoptosis control by death and decoy receptors. Curr Opin Cell Biol 1999;11(2):255–60.
  • Lee J, Huang M-S, Yang I-C, Lai T-C, Wang J-L, Pang VF, et al. Essential roles of caspases and their upstream regulators in rotenone-induced apoptosis. Biochem Biophys Res Commun 2008;371(1):33–8.
  • Yang F, Sun X, Beech W, Teter B, Wu S, Sigel J, et al. Antibody to caspase-cleaved actin detects apoptosis in differentiated neuroblastoma and plaque-associated neurons and microglia in Alzheimer’s disease. Am J Pathol 1998;152(2):379.
  • Venkatesan R, Park YU, Ji E, Yeo E-J, Kim SY. Malathion increases apoptotic cell death by inducing lysosomal membrane permeabilization in N2a neuroblastoma cells: a model for neurodegeneration in Alzheimer’s disease. Cell Death Discov 2017;3:17007.
  • Ahmed E, Nagaoka K, Fayez M, Abdel-Daim MM, Samir H, Watanabe G. Suppressive effects of long-term exposure to P-nitrophenol on gonadal development, hormonal profile with disruption of tissue integrity, and activation of caspase-3 in male Japanese quail (Coturnix japonica). Environ Sci Pollut Res 2015;22(14):10930–42.
  • Gervais FG, Xu D, Robertson GS, Vaillancourt JP, Zhu Y, Huang J, et al. Involvement of caspases in proteolytic cleavage of Alzheimer’s amyloid-β precursor protein and amyloidogenic Aβ peptide formation. Cell 1999;97(3):395–406.
  • Rohn TT, Head E, Su JH, Anderson AJ, Bahr BA, Cotman CW, et al. Correlation between caspase activation and neurofibrillary tangle formation in Alzheimer’s disease. Am J Pathol 2001;158(1):189–98.
  • Hwang L, Choi I-Y, Kim S-E, Ko I-G, Shin M-S, Kim C-J, et al. Dexmedetomidine ameliorates intracerebral hemorrhage-induced memory impairment by inhibiting apoptosis and enhancing brain-derived neurotrophic factor expression in the rat hippocampus. Int J Mol Med 2013;31(5):1047–56.
  • Manda K, Ueno M, Anzai K. Memory impairment, oxidative damage and apoptosis induced by space radiation: ameliorative potential of α-lipoic acid. Behav Brain Res 2008;187(2):387–95.
  • Sim Y-J, Kim S-S, Kim J-Y, Shin M-S, Kim C-J. Treadmill exercise improves short-term memory by suppressing ischemia-induced apoptosis of neuronal cells in gerbils. Neurosci Lett 2004;372(3):256–61.
  • Kumar V, Bhat Z, Kumar D, Khan N, Chashoo I, Shah M. Pharmacological profile of Crocus sativus–a comprehensive review. Pharmacologyonline 2011;3:799–811.
  • Ochiai T, Ohno S, Soeda S, Tanaka H, Shoyama Y, Shimeno H. Crocin prevents the death of rat pheochromyctoma (PC-12) cells by its antioxidant effects stronger than those of α-tocopherol. Neurosci Lett 2004;362(1):61–4.

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