Carvacrol Ameliorating Effects on Trimethyltin Chloride-Induced Neurotoxicity by Modulating the Interplay between Nrf2/Keap1/ARE Pathway and Sirt1

Document Type : Original paper

Authors

1 Department of Anatomy, School of Medicine, Arak University of Medical Sciences, Arak, Iran.

2 Traditional Medicine and Materia Medica Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

3 Research Center and Molecular Medicine, Arak University of Medical Sciences, Arak, Iran.

4 Department of Biochemistry and Genetics, School of Medicine, Arak University of Medical Sciences, Arak, Iran.

Abstract

Background and objectives: Trimethyltin chloride (TMT) is a chemical with neurotoxic effects on central nervous system. Carvacrol is a phenolic monoterpenoid with antioxidative properties derived from oregano, thyme, and other plants. We aimed to explore carvacrol effects on TMT-induced oxidative damage focusing on nuclear factor erythroid 2-related factor 2 (Nrf2)/ kelch-like ECH associated protein 1 (Keap1)/antioxidant response element (ARE) pathway and Sirt1. Methods: Thirty- two male rats were divided into four equal groups. Groups 1 and 2 received normal saline (control) and Dimethyl sulfoxide (DMSO, sham) for 21 days, respectively. Groups 3 and 4 were first treated with TMT (8 mg/kg) and then received normal saline and carvacrol (40 mg/kg) for 21 days, respectively. Finally, the levels of malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidant status (TOS) in serums and expressions of Nrf2, heme oxygenase-1 (Ho-1), Keap1, NADPH quinone oxidoreductase (NQO-1) and Sirtuin1 (Sirt1) in the hippocampus of the rats were quantified. Results: TMT significantly decreased Nrf2, HO1, NQO1, Sirt1 expressions and TAC level, while markedly increased expression of Keap-1 and levels MDA and TOS compared with control groups. Carvacrol treatment significantly upregulated Nrf2, HO1, NQO1, and Sirt1 along with an increase in TAC level as compared with TMT-treated rats. On the other hand, carvacrol caused a significant decrease in the expression of Keap-1 and levels of MDA and TOS compared with controls. Conclusion: Our results suggested the potential neuroprotective effects of carvacrol on TMT-triggered neurotoxicity probably by reciprocal regulation of Keap1/Nrf2/ARE pathway and Sirt1 activity.

Keywords

Main Subjects


  • Singh A, Kukreti R, Saso L, Kukreti S. Oxidative stress: a key modulator in neurodegenerative diseases. 2019; 24(8): 1–20.
  • Ghaffari S, Hatami H, Dehghan G. Saffron ethanolic extract attenuates oxidative stress, spatial learning, and memory impairments induced by local injection of ethidium bromide. Res Pharm Sci. 2015; 10(3): 222–232.
  • Huang TT, Leu D, Zou Y. Oxidative stress and redox regulation on hippocampal-dependent cognitive functions. Arch Biochem Biophys. 2015; 576: 2–7.
  • Bahaeddin Z, Yans A, Khodagholi F, Hajimehdipoor H, Sahranavard S. Hazelnut and neuroprotection: improved memory and hindered anxiety in response to intra-hippocampal Aβ injection. Nutr Neurosci. 2017; 20(6): 317–326.
  • Soodi M, Saeidnia S, Sharifzadeh M, Hajimehdipoor H, Dashti A, Sepand MR, Moradi S. Satureja bachtiarica ameliorate beta-amyloid induced memory impairment, oxidative stress and cholinergic deficit in animal model of Alzheimer’s disease. Metab Brain Dis. 2016; 31(2): 395–404.
  • Lobo V, Patil A, Phatak A, Chandra N. Free radicals, antioxidants and functional foods: impact on human health. Pharmacogn Rev. 2010; 4(8): 118–126.
  • Salehi S, Bayatiani M, Yaghmaei P, Rajabi S, Goodarzi M, Jalali Mashayekhi F. Protective effects of resveratrol against X-ray irradiation by regulating antioxidant defense system. 2018; 53(4): 293–298.
  • Chen J, Huang C, Zheng L, Simonich M, Bai C, Tanguay R, Dong Trimethyltin chloride (TMT) neurobehavioral toxicity in embryonic zebrafish. Neurotoxicol Teratol. 2011; 33(6): 721–726.
  • Ferraz da Silva I, Freitas Lima LC, Graceli JB, Rodrigues LCM. Organotins in neuronal damage, brain function, and behavior: a short review. Front Endocrinol (Lausanne). 2017; 8: 1–6.
  • Kim J, Kim CY, Oh H, Ryu B, Kim U, Min Lee J, Jung CR, Park Trimethyltin chloride induces reactive oxygen species-mediated apoptosis in retinal cells during zebrafish eye development. Sci Total Environ. 2019; 653: 36–44.
  • Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007; 47: 89–116.
  • David JA, Rifkin WJ, Rabbani PS, Ceradini DJ. The Nrf2/Keap1/ARE pathway and oxidative stress as a therapeutic target in type II diabetes mellitus. J Diabetes Res. 2017; Article ID 4826724.
  • Huang K, Gao X, Wei W. The crosstalk between Sirt1 and Keap1/Nrf2/ARE anti-oxidative pathway forms a positive feedback loop to inhibit FN and TGF-beta1 expressions in rat glomerular mesangial cells. Exp Cell Res. 2017; 361(1): 63–72.
  • Rahvar M, Owji AA, Mashayekhi FJ. Effect of quercetin on the brain-derived neurotrophic factor gene expression in the rat brain. Bratisl Lek Listy. 2018; 119(1): 28–31.
  • Ma Y, Ma B, Shang Y, Yin Q, Wang D, Xu S, Hong Y, Hou X, Liu X. Flavonoid-rich ethanol extract from the leaves of Diospyros kaki attenuates cognitive deficits, amyloid-beta production, oxidative stress, and neuroinflammation in APP/PS1 transgenic mice. Brain Res. 2018; 1678: 85–93.
  • Sharifi-Rad M, Varoni EM, Iriti M, Martorell M, Setzer WN, Contreras MDM, Salehi B, Soltani-Nejad A, Rajabi S, Tajbakhsh M, Sharifi-Rad Carvacrol and human health: a comprehensive review. Phytother Res. 2018; 32(9): 1675–1687.
  • Wang P, Luo Q, Qiao H, Ding H, Cao Y, Yu J, Liu R, Zhang Q, Zhu H, Qu L. The neuroprotective effects of carvacrol on ethanol-induced hippocampal neurons impairment via the antioxidative and antiapoptotic pathways. Oxid Med Cell Longev. 2017; Article ID 4079425.
  • Samarghandian S, Farkhondeh T, Samini F, Borji A. Protective effects of carvacrol against oxidative stress induced by chronic stress in rat's brain, liver, and kidney. Biochem Res Int. 2016; Article ID 2645237.
  • Shin EJ, Suh SK, Lim YK, Jhoo WK, Hjelle OP, Ottersen OP, Shin CY, Ko KH, Kim WK, Kim DS, Chun W, Ali S, Kim Ascorbate attenuates trimethyltin-induced oxidative burden and neuronal degeneration in the rat hippocampus by maintaining glutathione homeostasis. Neuroscience. 2005; 133(3): 715–727.
  • Kara M, Uslu S, Demirci F, Temel HE, Baydemir C. Supplemental carvacrol can reduce the severity of inflammation by influencing the production of mediators of inflammation. 2015; 38(3): 1020–1027.
  • Baranauskaite J, Sadauskiene I, Liekis A, Kasauskas A, Lazauskas R, Zlabiene U, Masteikova R, Kopustinskiene DM, Bernatoniene Natural compounds rosmarinic acid and carvacrol counteract aluminium-induced oxidative stress. Molecules. 2020; 25(8): 1–13.
  • Satoh K. Serum lipid peroxide in cerebrovascular disorders determined by a new colorimetric method. Clin Chim Acta. 1978; 90(1): 37–43.
  • Benzie IF, Strain JJ. Ferric reducing/antioxidant power assay: direct measure of total antioxidant activity of biological fluids and modified version for simultaneous measurement of total antioxidant power and ascorbic acid concentration. Methods Enzymol. 1999; 299: 15–27.
  • Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem. 2005; 38(12): 1103–1111.
  • Sakhaie MH, Soleimani M, Pirhajati V, Soleimani Asl S, Madjd Z, Mehdizadeh M. Coenzyme Q10 ameliorates trimethyltin chloride neurotoxicity in experimental model of injury in dentate gyrus of hippocampus: a histopathological and behavioral study. Iran Red Crescent Med J. 2016; 18(8): 1–8.
  • Samimi F, Baazm M, Eftekhar E, Rajabi S, Goodarzi MT, Jalali Mashayekhi F. Possible antioxidant mechanism of coenzyme Q10 in diabetes: impact on Sirt1/Nrf2 signaling pathways. Res Pharm Sci. 2019; 14(6): 524–533.
  • Yoneyama M, Nishiyama N, Shuto M, Sugiyama C, Kawada K, Seko K, Nagashima R, Ogita In vivo depletion of endogenous glutathione facilitates trimethyltin-induced neuronal damage in the dentate gyrus of mice by enhancing oxidative stress. Neurochem Int. 2008; 52(4-5): 761–769.
  • Liang YF, Qing Y, Du QQ, Fan P, Xu YP, Xu HG, Shi Study on mechanism of trimethyltin chloride-induced apoptosis in PC12 cells. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2012; 30(11): 816–819.
  • Zhao W, Pan X, Li T, Zhang C, Shi N. Lycium barbarum polysaccharides protect against trimethyltin chloride-induced apoptosis via sonic hedgehog and PI3K/Akt signaling pathways in mouse Neuro-2a cells. Oxid Med Cell Longev. 2016; Article ID 9826726.
  • Lattanzi W, Corvino V, Di Maria V, Michetti F, Geloso MC. Gene expression profiling as a tool to investigate the molecular machinery activated during hippocampal neurodegeneration induced by trimethyltin (TMT) administration. Int J Mol Sci. 2013; 14(8): 16817–16835.
  • Long J, Wang Q, He H, Sui X, Lin G, Wang S, Yang J, You P, Luo Y, Wang NLRP3 inflammasome activation is involved in trimethyltin-induced neuroinflammation. Brain Res. 2019; 1718: 186–193.
  • Gunes S, Ayhanci A, Sahinturk V, Altay DU, Uyar R. Carvacrol attenuates cyclophosphamide-induced oxidative stress in rat kidney. Can J Physiol Pharmacol. 2017; 95(7): 844–849.
  • Zou Y, Wang J, Peng J, Wei H. Oregano essential oil induces SOD1 and GSH expression through Nrf2 activation and alleviates hydrogen peroxide-induced oxidative damage in IPEC-J2 cells. Oxid Med Cell Longev. 2016; Article ID 5987183.