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Protein & Peptide Letters


ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

Research Article

Resveratrol Regulates Nrf2-Mediated Expression of Antioxidant and Xenobiotic Metabolizing Enzymes in Pesticides-Induced Parkinsonism

Author(s): Mohd Sami Ur Rasheed, Manish Kumar Tripathi, Devendra Kumar Patel and Mahendra Pratap Singh*

Volume 27 , Issue 10 , 2020

Page: [1038 - 1045] Pages: 8

DOI: 10.2174/0929866527666200403110036

Price: $65


Background: Combined maneb (MB) and paraquat (PQ), two widely used pesticides, increases oxidative stress leading to Parkinsonism. Xenobiotic metabolizing enzymes, cytochrome P450 (CYP) 2D6 and its mouse ortholog Cyp2d22 protect against Parkinsonism. Resveratrol, an antioxidant, restores antioxidant defense system through the activation of nuclear factor erythroid 2- related factor 2 (Nrf2). However, a crosstalk between Cyp2d22/CYP2D6-mediated protection and resveratrol-induced Nrf2 activation leading to neuroprotection is not yet elucidated.

Objective: The study aimed to decipher the effect of resveratrol on Nrf2 activation and expression of its downstream mediators, nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1 (NQO1) and thioredoxin 1 (Trx1) along with Cyp2d22/CYP2D6 activity in combined MB and PQ mouse model of Parkinsonism and differentiated neuroblastoma cells.

Results: MB and PQ reduced the dopamine content (mouse) and Cyp2d22/CYP2D6 activity (mouse/neuroblastoma cells) and increased the nuclear translocation of Nrf2 and expression of NQO1 and Trx1 (both). Resveratrol ameliorated pesticides-induced changes in dopamine content and Cyp2d22/CYP2D6 activity. It was found to promote nuclear translocation of Nrf2 and expression of NQO1 and Trx1 proteins. Since Cyp2d22/CYP2D6 inhibitor (ketoconazole/quinidine) per se reduced Cyp2d22/CYP2D6 activity and dopamine content, it was found to substantially increase the pesticides-induced reduction in Cyp2d22/CYP2D6 activity and dopamine content. Inhibitors normalized the pesticides induced changes in Nrf2 translocation and NQO1 and Trx1 levels in pesticides treated groups.

Conclusion: The results suggest that resveratrol promotes the catalytic activity of xenobiotic metabolizing enzyme, Cyp2d22/CYP2D6, which partially contributes to Nrf2 activation in pesticides- induced Parkinsonism.

Keywords: Combined maneb (MB), paraquat (PQ), resveratrol, Nrf2, Cyp2d22, CYP2D6.

Graphical Abstract
Berlett, B.S.; Stadtman, E.R. Protein oxidation in aging, disease, and oxidative stress. J. Biol. Chem., 1997, 272(33), 20313-20316.
[ ] [PMID: 9252331]
Singh, A.K.; Tiwari, M.N.; Upadhyay, G.; Patel, D.K.; Singh, D.; Prakash, O.; Singh, M.P. Long term exposure to cypermethrin induces nigrostriatal dopaminergic neurodegeneration in adult rats: Postnatal exposure enhances the susceptibility during adulthood. Neurobiol. Aging, 2012, 33(2), 404-415.
[ ] [PMID: 20371137]
Hastings, T.G. The role of dopamine oxidation in mitochondrial dysfunction: Implications for Parkinson’s disease. J. Bioenerg. Biomembr., 2009, 41(6), 469-472.
[ ] [PMID: 19967436]
Hatcher, J.M.; Pennell, K.D.; Miller, G.W. Parkinson’s disease and pesticides: A toxicological perspective. Trends Pharmacol. Sci., 2008, 29(6), 322-329.
[ ] [PMID: 18453001]
Berry, C.; La Vecchia, C.; Nicotera, P. Paraquat and Parkinson’s disease. Cell Death Differ., 2010, 17(7), 1115-1125.
[ ] [PMID: 20094060]
Barlow, B.K.; Lee, D.W.; Cory-Slechta, D.A.; Opanashuk, L.A. Modulation of antioxidant defense systems by the environmental pesticide maneb in dopaminergic cells. Neurotoxicology, 2005, 26(1), 63-75.
[ ] [PMID: 15527874]
Srivastava, G.; Dixit, A.; Yadav, S.; Patel, D.K.; Prakash, O.; Singh, M.P. Resveratrol potentiates cytochrome P450 2 d22-mediated neuroprotection in maneb- and paraquat-induced parkinsonism in the mouse. Free Radic. Biol. Med., 2012, 52(8), 1294-1306.
[ ] [PMID: 22334051]
Srivastava, G.; Singh, K.; Tiwari, M.N.; Singh, M.P. Proteomics in Parkinson’s disease: Current trends, translational snags and future possibilities. Expert Rev. Proteomics, 2010, 7(1), 127-139.
[ ] [PMID: 20121482]
Patel, S.; Singh, V.; Kumar, A.; Gupta, Y.K.; Singh, M.P. Status of antioxidant defense system and expression of toxicant responsive genes in striatum of maneb- and paraquat-induced Parkinson’s disease phenotype in mouse: Mechanism of neurodegeneration. Brain Res., 2006, 1081(1), 9-18.
[ ] [PMID: 16510128]
Zordoky, B.N.; Robertson, I.M.; Dyck, J.R. Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases. Biochim. Biophys. Acta, 2015, 1852(6), 1155-1177.
[ ] [PMID: 25451966]
Albani, D.; Polito, L.; Batelli, S.; De Mauro, S.; Fracasso, C.; Martelli, G.; Colombo, L.; Manzoni, C.; Salmona, M.; Caccia, S.; Negro, A.; Forloni, G. The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused by α-synuclein or amyloid-β (1-42) peptide. J. Neurochem., 2009, 110(5), 1445-1456.
[ ] [PMID: 19558452]
Shin, S.M.; Cho, I.J.; Kim, S.G. Resveratrol protects mitochondria against oxidative stress through AMP-activated protein kinase-mediated glycogen synthase kinase-3beta inhibition downstream of poly(ADP-ribose)polymerase-LKB1 pathway. Mol. Pharmacol., 2009, 76(4), 884-895.
[ ] [PMID: 19620254]
Jin, F.; Wu, Q.; Lu, Y.F.; Gong, Q.H.; Shi, J.S. Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson’s disease in rats. Eur. J. Pharmacol., 2008, 600(1-3), 78-82.
[ ] [PMID: 18940189]
Ur Rasheed, M.S.; Mishra, A.K.; Singh, M.P. Cytochrome P450 2D6 and Parkinson’s disease: Polymorphism, metabolic role, risk and protection. Neurochem. Res., 2017, 42(12), 3353-3361.
[ ] [PMID: 28871472]
Singh, S.; Singh, K.; Patel, D.K.; Singh, C.; Nath, C.; Singh, V.K.; Singh, R.K.; Singh, M.P. The expression of CYP2D22, an ortholog of human CYP2D6, in mouse striatum and its modulation in 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine- induced Parkinson’s disease phenotype and nicotine-mediated neuroprotection. Rejuvenation Res., 2009, 12(3), 185-197.
[ ] [PMID: 19594327]
Elbaz, A.; Levecque, C.; Clavel, J.; Vidal, J.S.; Richard, F.; Amouyel, P.; Alpérovitch, A.; Chartier-Harlin, M.C.; Tzourio, C. CYP2D6 polymorphism, pesticide exposure, and Parkinson’s disease. Ann. Neurol., 2004, 55(3), 430-434.
[ ] [PMID: 14991823]
Huang, H.C.; Nguyen, T.; Pickett, C.B. Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription. J. Biol. Chem., 2002, 277(45), 42769-42774.
[ ] [PMID: 12198130]
Li, H.Y.; Wu, S.Y.; Ma, Q.; Shi, N. The pesticide deltamethrin increases free radical production and promotes nuclear translocation of the stress response transcription factor Nrf2 in rat brain. Toxicol. Ind. Health, 2011, 27(7), 579-590.
[ ] [PMID: 21398409]
Im, J.Y.; Lee, K.W.; Woo, J.M.; Junn, E.; Mouradian, M.M. DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway. Hum. Mol. Genet., 2012, 21(13), 3013-3024.
[ ] [PMID: 22492997]
van Muiswinkel, F.L.; de Vos, R.A.; Bol, J.G.; Andringa, G.; Jansen Steur, E.N.; Ross, D.; Siegel, D.; Drukarch, B. Expression of NAD(P)H: Quinone oxidoreductase in the normal and Parkinsonian substantia nigra. Neurobiol. Aging, 2004, 25(9), 1253-1262.
[ ] [PMID: 15312971]
Drukarch, B.; van Muiswinkel, F.L. Drug treatment of Parkinson’s disease. Time for phase II. Biochem. Pharmacol., 2000, 59(9), 1023-1031.
[ ] [PMID: 10704931]
Kim, E.N.; Lim, J.H.; Kim, M.Y.; Ban, T.H.; Jang, I.A.; Yoon, H.E.; Park, C.W.; Chang, Y.S.; Choi, B.S. Resveratrol, an Nrf2 activator, ameliorates aging-related progressive renal injury. Aging (Albany NY), 2018, 10(1), 83-99.
[ ] [PMID: 29326403]
Hsieh, T.C.; Lu, X.; Wang, Z.; Wu, J.M. Induction of quinone reductase NQO1 by resveratrol in human K562 cells involves the antioxidant response element ARE and is accompanied by nuclear translocation of transcription factor Nrf2. Med. Chem., 2006, 2(3), 275-285.
[ ] [PMID: 16948474]
Mobasher, M.A.; González-Rodriguez, A.; Santamaría, B.; Ramos, S.; Martín, M.Á.; Goya, L.; Rada, P.; Letzig, L.; James, L.P.; Cuadrado, A.; Martín-Pérez, J.; Simpson, K.J.; Muntané, J.; Valverde, A.M. Protein tyrosine phosphatase 1B modulates GSK3β/Nrf2 and IGFIR signaling pathways in acetaminophen-induced hepatotoxicity. Cell Death Dis., 2013, 4, e626.
[ ] [PMID: 23661004]
Lowry, O.H.; Rosebrough, N.J.; Farr, A.L.; Randall, R.J. Protein measurement with the Folin phenol reagent. J. Biol. Chem., 1951, 193(1), 265-275.
[PMID: 14907713]
Mishra, A.K.; Mishra, S.; Rajput, C.; Ur Rasheed, M.S.; Patel, D.K.; Singh, M.P. Cypermethrin activates autophagosome formation albeit inhibits autophagy owing to poor lysosome quality: Relevance to Parkinson’s disease. Neurotox. Res., 2018, 33(2), 377-387.
[ ] [PMID: 28840510]
McLaughlin, L.A.; Dickmann, L.J.; Wolf, C.R.; Henderson, C.J. Functional expression and comparative characterization of nine murine cytochromes P450 by fluorescent inhibition screening. Drug Metab. Dispos., 2008, 36(7), 1322-1331.
[ ] [PMID: 18420780]
Dou, T.; Yan, M.; Wang, X.; Lu, W.; Zhao, L.; Lou, D.; Wu, C.; Chang, X.; Zhou, Z. Nrf2/ARE Pathway involved in oxidative stress induced by paraquat in human neural progenitor cells. Oxid. Med. Cell. Longev., 2016, 2016, 8923860.
[ ] [PMID: 26649146]
Ramsey, C.P.; Glass, C.A.; Montgomery, M.B.; Lindl, K.A.; Ritson, G.P.; Chia, L.A.; Hamilton, R.L.; Chu, C.T.; Jordan-Sciutto, K.L. Expression of Nrf2 in neurodegenerative diseases. J. Neuropathol. Exp. Neurol., 2007, 66(1), 75-85.
[ ] [PMID: 17204939]
Kode, A.; Rajendrasozhan, S.; Caito, S.; Yang, S.R.; Megson, I.L.; Rahman, I. Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol., 2008, 294(3), L478-L488.
[ ] [PMID: 18162601]
Kovalevich, J.; Langford, D. Considerations for the use of SH-SY5Y neuroblastoma cells in neurobiology. Methods Mol. Biol., 2013, 1078, 9-21.
[ ] [PMID: 23975817]
Mann, A.; Tyndale, R.F. Cytochrome P450 2D6 enzyme neuroprotects against 1-methyl-4-phenylpyridinium toxicity in SH-SY5Y neuronal cells. Eur. J. Neurosci., 2010, 31(31), 1185-1193.
[] [PMID: 20345925]

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