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Neuroprotective effects of 18β-glycyrrhetinic acid against bisphenol A-induced neurotoxicity in rats: involvement of neuronal apoptosis, endoplasmic reticulum stress and JAK1/STAT1 signaling pathway

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Abstract

The exposure to bisphenol A (BPA) is inevitable owing to its common use in the production of polycarbonate plastics. Studies to reduce side effects are gaining importance since BPA causes severe toxicities in important tissues such as testes, lungs, brain, liver and kidney. The current study was planned to study ameliorative effect of 18β-glycyrrhetinic acid (18β-GA) on BPA induced neurotoxicity. Fourty Wistar albino rats were divided into five equal groups as follows: I-Control group, II-18β-GA group (100 mg/kg), III- BPA group (250 mg/kg), IV-250 mg/kg BPA + 50 mg/kg 18β-GA group, V-250 mg/kg BPA + 100 mg/kg 18β-GA group. BPA intoxication was associated with increased MDA level while reduced GSH concentration, activities of glutathione peroxidase, superoxide dismutase, and catalase. BPA supplementation caused apoptosis in the brain by up-regulating caspase-3 and Bax levels and down-regulating Bcl-2. BPA also caused endoplasmic reticulum (ER) stress by increasing mRNA transcript levels of PERK, IRE1, ATF-6 and GRP78. Additionally, it was observed that BPA administration activated JAK1/STAT1 signaling pathway and levels of TNF-α, NF-κB, p38 MAPK and JNK in the brain. However, co-treatment with 18β-GA at a dose of 50 and 100 mg/kg considerably ameliorated oxidative stress, inflammation, apoptosis, ER stress and JAK1/STAT1 signaling pathway in brain tissue. Overall, the data of this study indicate that brain damage associated with BPA toxicity could be ameliorated by 18β-GA administration.

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References

  • Abraham A, Chakraborty P (2020) A review on sources and health impacts of bisphenol A. Rev Environ Health 35:201–210

    Article  CAS  PubMed  Google Scholar 

  • Aebi H (1984) [13] Catalase in vitro. Methods Enzymol 105:121–126

    Article  CAS  PubMed  Google Scholar 

  • Alanazi IS, Emam M, Elsabagh M, Alkahtani S, Abdel-Daim MM (2021) The protective effects of 18β-glycyrrhetinic acid against acrylamide-induced cellular damage in diabetic rats. Environ Sci Pollut Res 28:58322–58330

    Article  CAS  Google Scholar 

  • Almeida S, Raposo A, Almeida-González M, Carrascosa C (2018) Bisphenol A: food exposure and impact on human health. Compr Rev Food Sci Food Saf 17:1503–1517

    Article  PubMed  Google Scholar 

  • Ayna A (2021) Caffeic acid prevents hydrogen peroxide-induced oxidative damage in SH-SY5Y cell line through mitigation of oxidative stress and apoptosis. Bratisl Lek List 122:120–124

    CAS  Google Scholar 

  • Berger A, Ziv-Gal A, Cudiamat J, Wang W, Zhou C, Flaws JA (2016) The effects of in utero bisphenol A exposure on the ovaries in multiple generations of mice. Reprod Toxicol 60:39–52

    Article  CAS  PubMed  Google Scholar 

  • Bhandary B, Marahatta A, Kim H-R, Chae H-J (2013) An involvement of oxidative stress in endoplasmic reticulum stress and its associated diseases. Int J Mol Sci 14

  • Bursal E, Köksal E, Gülçin İ, Bilsel G, Gören AC (2013) Antioxidant activity and polyphenol content of cherry stem (Cerasus avium L.) determined by LC–MS/MS. Food Res Int 51:66–74

    Article  CAS  Google Scholar 

  • Caglayan C, Temel Y, Kandemir FM, Yildirim S, Kucukler S (2018) Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage. Environ Sci Pollut Res 25:20968–20984

    Article  CAS  Google Scholar 

  • Çağlayan C, Taslimi P, Demir Y, Küçükler S, Kandemir FM, Gulçin İ (2019) The effects of zingerone against vancomycin-induced lung, liver, kidney and testis toxicity in rats: the behavior of some metabolic enzymes. J Biochem Mol Toxicol 33:e22381

    Article  PubMed  CAS  Google Scholar 

  • Caglayan C, Kandemir FM, Darendelioğlu E, Küçükler S, Ayna A (2021) Hesperidin protects liver and kidney against sodium fluoride-induced toxicity through anti-apoptotic and anti-autophagic mechanisms. Life Sci 281:119730

    Article  CAS  PubMed  Google Scholar 

  • Cao Y, Sa T, Nie X, Zhou Z, Ruan G, Han W et al (2021) Decreased miR-214–3p activates NF-κB pathway and aggravates osteoarthritis progression. EBioMedicine 65:103283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Çelik H, Kandemir FM, Caglayan C, Özdemir S, Çomaklı S, Kucukler S et al (2020a) Neuroprotective effect of rutin against colistin-induced oxidative stress, inflammation and apoptosis in rat brain associated with the CREB/BDNF expressions. Mol Biol Rep 47:2023–2034

    Article  PubMed  CAS  Google Scholar 

  • Çelik H, Kucukler S, Çomaklı S, Caglayan C, Özdemir S, Yardım A et al (2020b) Neuroprotective effect of chrysin on isoniazid-induced neurotoxicity via suppression of oxidative stress, inflammation and apoptosis in rats. NeuroToxicology 81:197–208

    Article  PubMed  CAS  Google Scholar 

  • Ceylan H, Demir Y, Beydemir Ş (2019) Inhibitory effects of usnic and carnosic acid on some metabolic enzymes: an in vitro study. Protein Pept Lett 26:364–370

    Article  CAS  PubMed  Google Scholar 

  • Dwivedi D, Megha K, Mishra R, Mandal PK (2020) Glutathione in brain: overview of its conformations, functions, biochemical characteristics, quantitation and potential therapeutic role in brain disorders. Neurochem Res 45:1461–1480

    Article  CAS  PubMed  Google Scholar 

  • Eweda SM, Newairy ASA, Abdou HM, Gaber AS (2020) Bisphenol A-induced oxidative damage in the hepatic and cardiac tissues of rats: the modulatory role of sesame lignans. Exp Ther Med 19:33–44

    CAS  PubMed  Google Scholar 

  • Gassman NR (2017) Induction of oxidative stress by bisphenol A and its pleiotropic effects. Environ Mol Mutagen 58:60–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geng S, Wang S, Zhu W, Xie C, Li X, Wu J et al (2018) Curcumin suppresses JNK pathway to attenuate BPA-induced insulin resistance in LO2 cells. Biomed Pharmacother 97:1538–1543

    Article  CAS  PubMed  Google Scholar 

  • Gulcin I (2012) Antioxidant activity of food constituents: an overview. Arch Toxicol 86:345–391

    Article  PubMed  CAS  Google Scholar 

  • Gulcin İ (2020) Antioxidants and antioxidant methods: an updated overview. Arch Toxicol 94:651–715

    Article  CAS  PubMed  Google Scholar 

  • Gülçin İ, Topal F, Sarikaya SBÖ, Bursal E, Bilsel G, Gören AC (2011) Polyphenol contents and antioxidant properties of Medlar (Mespilus germanica L.). Rec Nat Prod 5:158

    Google Scholar 

  • Gur C, Kandemir FM, Darendelioglu E, Caglayan C, Kucukler S, Kandemir O et al (2021) Morin protects against acrylamide-induced neurotoxicity in rats: an investigation into different signal pathways. Environ Sci Pollut Res

  • Hasan SK, Siddiqi A, Nafees S, Ali N, Rashid S, Ali R et al (2016) Chemopreventive effect of 18β-glycyrrhetinic acid via modulation of inflammatory markers and induction of apoptosis in human hepatoma cell line (HepG2). Mol Cell Biochem 416:169–177

    Article  CAS  PubMed  Google Scholar 

  • Kabuto H, Amakawa M, Shishibori T (2004) Exposure to bisphenol A during embryonic/fetal life and infancy increases oxidative injury and causes underdevelopment of the brain and testis in mice. Life Sci 74:2931–2940

    Article  CAS  PubMed  Google Scholar 

  • Kirici M, Turk C, Caglayan C, Kirici M (2017) Toxic effects of copper sulphate pentahydrate on antioxidant enzyme activities and lipid peroxidation of freshwater fish Capoeta umbla (Heckel, 1843) tissues. Appl Ecol Environ Res 15:1685–1696

    Article  Google Scholar 

  • Kopp MC, Larburu N, Durairaj V, Adams CJ, Ali MMU (2019) UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor. Nat Struct Mol Biol 26:1053–1062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kowalska A, Kalinowska-Lis U (2019) 18β-Glycyrrhetinic acid: its core biological properties and dermatological applications. Int J Cosmet Sci 41:325–331

    CAS  PubMed  Google Scholar 

  • Kucukler S, Caglayan C, Darendelioğlu E, Kandemir FM (2020a) Morin attenuates acrylamide-induced testicular toxicity in rats by regulating the NF-κB, Bax/Bcl-2 and PI3K/Akt/mTOR signaling pathways. Life Sci 261:118301

    Article  CAS  PubMed  Google Scholar 

  • Kucukler S, Darendelioğlu E, Caglayan C, Ayna A, Yıldırım S, Kandemir FM (2020b) Zingerone attenuates vancomycin-induced hepatotoxicity in rats through regulation of oxidative stress, inflammation and apoptosis. Life Sci 259:118382

    Article  CAS  PubMed  Google Scholar 

  • Kuzu M, Kandemir FM, Yıldırım S, Çağlayan C, Küçükler S (2021) Attenuation of sodium arsenite-induced cardiotoxicity and neurotoxicity with the antioxidant, anti-inflammatory, and antiapoptotic effects of hesperidin. Environ Sci Pollut Res 28:10818–10831

    Article  CAS  Google Scholar 

  • Lawrence RA, Burk RF (1976) Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun 71:952–958

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Shi H, Xie B, Dionysiou DD, Zhao Y (2019) Microplastics as both a sink and a source of bisphenol A in the marine environment. Environ Sci Technol 53:10188–10196

    Article  CAS  PubMed  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    Article  CAS  PubMed  Google Scholar 

  • Lyras L, Cairns NJ, Jenner A, Jenner P, Halliwell B (1997) An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer's disease. J Neurochem 68:2061–2069

    Article  CAS  PubMed  Google Scholar 

  • Ma Y, Liu H, Wu J, Yuan L, Wang Y, Du X et al (2019) The adverse health effects of bisphenol A and related toxicity mechanisms. Environ Res 176:108575

    Article  CAS  PubMed  Google Scholar 

  • MacCorkle RA, Tan T-H (2005) Mitogen-activated protein kinases in cell-cycle control. Cell Biochem Biophys 43:451–461

    Article  CAS  PubMed  Google Scholar 

  • Mehrandish R, Rahimian A, Shahriary A (2019) Heavy metals detoxification: a review of herbal compounds for chelation therapy in heavy metals toxicity. J Herbmed Pharmacol 8:69–77

    Article  CAS  Google Scholar 

  • Mondal S, Bandyopadhyay A (2021) Bisphenol A and male murine reproductive system: finding a link between plasticizer and compromised health. Toxicol Sci 183:241–252

    Article  CAS  PubMed  Google Scholar 

  • Moreno-Gómez-Toledano R, Sánchez-Esteban S, Cook A, Mínguez-Moratinos M, Ramírez-Carracedo R, Reventún P et al (2021) Bisphenol A induces accelerated cell aging in murine endothelium. Biomolecules 11

  • Morris R, Kershaw NJ, Babon JJ (2018) The molecular details of cytokine signaling via the JAK/STAT pathway. Protein Sci 27:1984–2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ni Y, Hu L, Yang S, Ni L, Ma L, Zhao Y et al (2021) Bisphenol A impairs cognitive function and 5-HT metabolism in adult male mice by modulating the microbiota-gut-brain axis. Chemosphere 282:130952

    Article  CAS  PubMed  Google Scholar 

  • Pelch K, Wignall JA, Goldstone AE, Ross PK, Blain RB, Shapiro AJ et al (2019) A scoping review of the health and toxicological activity of bisphenol A (BPA) structural analogues and functional alternatives. Toxicology 424:152235

    Article  CAS  PubMed  Google Scholar 

  • Placer ZA, Cushman LL, Johnson BC (1966) Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem 16:359–364

    Article  CAS  PubMed  Google Scholar 

  • Polat Kose L, Gulcin İ (2021) Evaluation of the antioxidant and antiradical properties of some Phyto and mammalian Lignans. Molecules 26

  • Priego AR, Parra EG, Mas S, Morgado-Pascual JL, Ruiz-Ortega M, Rayego-Mateos S (2021) Bisphenol A modulates autophagy and exacerbates chronic kidney damage in mice. Int J Mol Sci 22

  • Rajmohan KS, Chandrasekaran R, Varjani S (2020) A review on occurrence of pesticides in environment and current technologies for their remediation and management. Indian J Microbiol 60:125–138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rashid S, Nafees S, Siddiqi A, Vafa A, Afzal SM, Parveen R et al (2017) Partial protection by 18β Glycrrhetinic acid against cisplatin induced oxidative intestinal damage in wistar rats: possible role of NFkB and caspases. Pharmacol Rep 69:1007–1013

    Article  CAS  PubMed  Google Scholar 

  • Rehman A, Akhtar T, Hameed N, Sheikh N (2020) In vivo assessment of bisphenol A induced histopathological alterations and inflammatory gene expression in lungs of male Wistar rats. Human & Experimental Toxicology 40:538–549

    Article  CAS  Google Scholar 

  • Sahoo PK, Pradhan LK, Aparna S, Agarwal K, Banerjee A, Das SK (2020) Quercetin abrogates bisphenol A induced altered neurobehavioral response and oxidative stress in zebrafish by modulating brain antioxidant defence system. Environ Toxicol Pharmacol 80:103483

    Article  CAS  PubMed  Google Scholar 

  • Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem 25:192–205

    Article  CAS  PubMed  Google Scholar 

  • Shen S, Zhou M, Huang K, Wu Y, Ma Y, Wang J et al (2017) Blocking autophagy enhances the apoptotic effect of 18β-glycyrrhetinic acid on human sarcoma cells via endoplasmic reticulum stress and JNK activation. Cell Death Dis 8:e3055–e3055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shirani M, Alizadeh S, Mahdavinia M, Dehghani MA (2019) The ameliorative effect of quercetin on bisphenol A-induced toxicity in mitochondria isolated from rats. Environ Sci Pollut Res 26:7688–7696

    Article  CAS  Google Scholar 

  • Stutzmann GE, Mattson MP (2011) Endoplasmic reticulum Ca2+ handling in excitable cells in health and disease. Pharmacol Rev 63:700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun Y, Oberley LW, Li Y (1988) A simple method for clinical assay of superoxide dismutase. Clin Chem 34:497–500

    Article  CAS  PubMed  Google Scholar 

  • Sun Y, Wang X, Zhou Y, Zhang J, Cui W, Wang E et al (2021) Protective effect of metformin on BPA-induced liver toxicity in rats through upregulation of cystathionine β synthase and cystathionine γ lyase expression. Sci Total Environ 750:141685

    Article  CAS  PubMed  Google Scholar 

  • Volpe CMO, Villar-Delfino PH, dos Anjos PMF, Nogueira-Machado JA (2018) Cellular death, reactive oxygen species (ROS) and diabetic complications. Cell Death Dis 9:119

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • vom Saal FS, Vandenberg LN (2021) Update on the health effects of bisphenol A: overwhelming evidence of harm. Endocrinology 162:bqaa171

    Article  PubMed  Google Scholar 

  • Wagner EF, Nebreda ÁR (2009) Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer 9:537–549

    Article  CAS  PubMed  Google Scholar 

  • Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334:1081–1086

    Article  CAS  PubMed  Google Scholar 

  • Wang S, Kaufman RJ (2012) The impact of the unfolded protein response on human disease. J Cell Biol 197:857–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X, Wang B, Fan Z, Shi X, Ke ZJ, Luo J (2007) Thiamine deficiency induces endoplasmic reticulum stress in neurons. Neuroscience 144:1045–1056

    Article  CAS  PubMed  Google Scholar 

  • Yardım A, Kucukler S, Özdemir S, Çomaklı S, Caglayan C, Kandemir FM et al (2021) Silymarin alleviates docetaxel-induced central and peripheral neurotoxicity by reducing oxidative stress, inflammation and apoptosis in rats. Gene 769:145239

    Article  PubMed  CAS  Google Scholar 

  • Yarza R, Vela S, Solas M, Ramirez MJ (2016) c-Jun N-terminal Kinase (JNK) signaling as a therapeutic target for Alzheimer’s disease. Front Pharmacol 6

  • Yeh C-H, Shih H-C, Hong H-M, Lee S-S, Yang M-L, Chen C-J et al (2013) Protective effect of wogonin on proinflammatory cytokine generation via Jak1/3-STAT1/3 pathway in lipopolysaccharide stimulated BV2 microglial cells. Toxicol Ind Health 31:960–966

    Article  PubMed  CAS  Google Scholar 

  • Yin L, Dai Y, Cui Z, Jiang X, Liu W, Han F et al (2017) The regulation of cellular apoptosis by the ROS-triggered PERK/EIF2α/chop pathway plays a vital role in bisphenol A-induced male reproductive toxicity. Toxicol Appl Pharmacol 314:98–108

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported by Scientific Research Projects Coordination Unit of Bingol University (Project number BAP-FEF.2020.00.006). Therefore, we are grateful to Bingol University, Turkey.

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Veterinary Medicine, Bingol University, 12000, Bingol, Turkey

    Cuneyt Caglayan

  2. Department of Medical Biochemistry, Faculty of Medicine, Aksaray University, Aksaray, Turkey

    Fatih Mehmet Kandemir

  3. Department of Chemistry, Faculty of Science and Literature, University Bingol, 12000, Bingol, Turkey

    Adnan Ayna

  4. Department of Biochemistry, Faculty of Veterinary Medicine, Atatürk University, 25240, Erzurum, Turkey

    Cihan Gür & Sefa Küçükler

  5. Department of Molecular Biology and Genetics, Faculty of Science and Literature, University Bingol, 12000, Bingol, Turkey

    Ekrem Darendelioğlu

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  1. Cuneyt Caglayan
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  3. Adnan Ayna
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  4. Cihan Gür
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CC, FMK and ED designed the research. CC and ED conducted experiments. FMK, CG, and SK analyzed data. CC and AA wrote the manuscript. All the authors have read and approved the final version for publication.

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Correspondence to Cuneyt Caglayan.

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Caglayan, C., Kandemir, F.M., Ayna, A. et al. Neuroprotective effects of 18β-glycyrrhetinic acid against bisphenol A-induced neurotoxicity in rats: involvement of neuronal apoptosis, endoplasmic reticulum stress and JAK1/STAT1 signaling pathway. Metab Brain Dis 37, 1931–1940 (2022). https://doi.org/10.1007/s11011-022-01027-z

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