Generic placeholder image

Current Drug Discovery Technologies

Editor-in-Chief

ISSN (Print): 1570-1638
ISSN (Online): 1875-6220

Research Article

Restoring Impaired Neurogenesis and Alleviating Oxidative Stress by Cyanidin against Bisphenol A-induced Neurotoxicity: In Vivo and In Vitro Evidence

Author(s): Swathi Suresh and Chitra Vellapandian*

Volume 21, Issue 2, 2024

Published on: 25 January, 2024

Article ID: e250124226256 Pages: 14

DOI: 10.2174/0115701638280481231228064532

Price: $65

conference banner
Abstract

Background: Bisphenol A (BPA) is a known neurotoxic compound with potentially harmful effects on the nervous system. Cyanidin (CYN) has shown promise as a neuroprotective agent.

Objective: The current study aims to determine the efficacy of CYN against BPA-induced neuropathology.

Methods: In vitro experiments utilized PC12 cells were pre-treated with gradient doses of CYN and further stimulated with 10ng/ml of BPA. DPPH radical scavenging activity, catalase activity, total ROS activity, and nitric oxide radical scavenging activity were done. In vivo assessments employed doublecortin immunohistochemistry of the brain in BPA-exposed Sprague-Dawley rats. Further, In silico molecular docking of CYN with all proteins involved in canonical Wnt signaling was performed using the Autodock v4.2 tool and BIOVIA Discovery Studio Visualizer.

Results: IC50 values of CYN and ascorbic acid were determined using dose-response curves, and it was found to be 24.68 ± 0.563 μg/ml and 20.69 ± 1.591μg/ml, respectively. BPA-stimulated cells pre-treated with CYN showed comparable catalase activity with cells pre-treated with ascorbic acid (p = 0.0287). The reactive species production by CYN-treated cells was significantly decreased compared to BPA-stimulated cells (p <0.0001). Moreover, CYN significantly inhibited nitric oxide production compared to BPA stimulated and the control cells (p < 0.0001). In vivo CYN positively affected immature neuron quantity, correlating with dosage. During molecular docking analysis, CYN exhibited a binding affinity > -7 Kcal/mol with all the key proteins associated with the Wnt/β- catenin signaling cascade.

Conclusion: Conclusively, our finding suggests that CYN exhibited promise in counteracting BPAinduced oxidative stress, improving compromised neurogenesis in hippocampal and cortical regions, and displaying notable interactions with Wnt signaling proteins. Thereby, CYN could render its neuroprotective potential against BPA-induced neuropathology.

Graphical Abstract

[1]
Suresh S, Singh SA, Vellapandian C. Bisphenol A exposure links to exacerbation of memory and cognitive impairment: A systematic review of the literature. Neurosci Biobehav Rev 2022; 143: 104939.
[http://dx.doi.org/10.1016/j.neubiorev.2022.104939] [PMID: 36328120]
[2]
Gowder S. Nephrotoxicity of bisphenol A (BPA)--an updated review. Curr Mol Pharmacol 2014; 6(3): 163-72.
[http://dx.doi.org/10.2174/1874467207666140410115823] [PMID: 24720537]
[3]
Huang CC, Yang CY, Su CC, et al. 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene, a major active metabolite of bisphenol A, Triggers Pancreatic β-Cell Death via a JNK/AMPKα activation-regulated endoplasmic reticulum stress-mediated apoptotic pathway. Int J Mol Sci 2021; 22(9): 4379. [Internet].
[http://dx.doi.org/10.3390/ijms22094379]
[4]
Santoro A, Chianese R, Troisi J, Richards S, Nori SL, Fasano S. Neuro-toxic and reproductive effects of BPA. Curr Neuropharmacol 2019; 17(12): 1109.
[http://dx.doi.org/10.2174/1570159X17666190726112101]
[5]
Banji OJF, Banji D, Makeen HA, Alqahtani SS, Alshahrani S. Neuroinflammation: The role of anthocyanins as neuroprotectants. Curr Neuropharmacol 2022; 20(11): 2156-74.
[http://dx.doi.org/10.2174/1570159X20666220119140835] [PMID: 35043761]
[6]
D. Maleknia S. M. Downard K. new anthocyanins from black elderberry of inhibitory potential revealed by mass spectrometry. Nat Prod J 2016; 6(2): 94-102.
[http://dx.doi.org/10.2174/2210315506666160115214231]
[7]
Suresh S, Begum RF, Singh SA. v C. Anthocyanin as a therapeutic in Alzheimer’s disease: A systematic review of preclinical evidences. Ageing Res Rev 2022; 76: 101595.
[http://dx.doi.org/10.1016/j.arr.2022.101595] [PMID: 35217244]
[8]
Shi MZ, Xie DY. Biosynthesis and metabolic engineering of anthocyanins in Arabidopsis thaliana. Recent Pat Biotechnol 2014; 8(1): 47-60.
[http://dx.doi.org/10.2174/1872208307666131218123538] [PMID: 24354533]
[9]
Shan X, Chen J, Dai S, et al. Cyanidin-related antidepressant-like efficacy requires PI3K/AKT/FoxG1/FGF-2 pathway modulated enhancement of neuronal differentiation and dendritic maturation. Phytomedicine 2020; 76: 153269.
[http://dx.doi.org/10.1016/j.phymed.2020.153269] [PMID: 32593103]
[10]
Thummayot S, Tocharus C, Jumnongprakhon P, Suksamrarn A, Tocharus J. Cyanidin attenuates Aβ25-35-induced neuroinflammation by suppressing NF-κB activity downstream of TLR4/NOX4 in human neuroblastoma cells. Acta Pharmacol Sin 2018; 39(9): 1439.
[11]
Tan L, Yang HP, Pang W, et al. Cyanidin-3-O-galactoside and blueberry extracts supplementation improves spatial memory and regulates hippocampal ERK expression in senescence-accelerated mice. Biomed Environ Sci 2014; 27(3): 186-96. [Internet].
[PMID: 24709099]
[12]
Agustin A, Safitri A, Fatchiyah F. An in silico approach reveals the potential function of cyanidin-3-o-glucoside of red rice in inhibiting the advanced glycation end products (AGES)-Receptor (RAGE) signaling pathway. Acta Inform Med 2020; 28(3): 170-9.
[http://dx.doi.org/10.5455/aim.2020.28.170-179] [PMID: 33417643]
[13]
Narvaes RF, Furini CRG. Role of Wnt signaling in synaptic plasticity and memory. Neurobiol Learn Mem 2022; 187: 107558.
[http://dx.doi.org/10.1016/j.nlm.2021.107558] [PMID: 34808336]
[14]
Laksitorini MD, Yathindranath V, Xiong W, Parkinson FE, Thliveris JA, Miller DW. Impact of Wnt/β‐catenin signaling on ethanol‐induced changes in brain endothelial cell permeability. J Neurochem 2021; 157(4): 1118-37.
[http://dx.doi.org/10.1111/jnc.15203] [PMID: 32998179]
[15]
Ortiz-Matamoros A, Salcedo-Tello P, Avila-Muñoz E, Zepeda A, Arias C. Role of wnt signaling in the control of adult hippocampal functioning in health and disease: Therapeutic implications. Curr Neuropharmacol 2013; 11(5): 465-76.
[http://dx.doi.org/10.2174/1570159X11311050001] [PMID: 24403870]
[16]
Suresh S, Vellapandian C. Cyanidin ameliorates bisphenol a-induced alzheimer’s disease pathology by restoring wnt/β-catenin signaling cascade: An in vitro study. Mol Neurobiol 2023; 1: 1-17.https://link.springer.com/article/10.1007/s12035-023-03672-6
[http://dx.doi.org/10.1007/s12035-023-03672-6] [PMID: 37843801]
[17]
Blois MS. Antioxidant determinations by the use of a stable free radical. Nat 1958; 181(4167): 1199-200.https://www.nature.com/articles/1811199a0
[http://dx.doi.org/10.1038/1811199a0]
[18]
Aebi H. Catalase in vitro. Methods Enzymol 1984; 105(C): 121-6.
[http://dx.doi.org/10.1016/S0076-6879(84)05016-3] [PMID: 6727660]
[19]
Mfotie Njoya E, Munvera AM, Mkounga P, Nkengfack AE, McGaw LJ. Phytochemical analysis with free radical scavenging, nitric oxide inhibition and antiproliferative activity of Sarcocephalus pobeguinii extracts. BMC Complement Altern Med 2017; 17(1)
[http://dx.doi.org/10.1186/s12906-017-1712-5]
[20]
Kim SW, Roh J, Park CS. Immunohistochemistry for Pathologists: Protocols, Pitfalls, and Tips. J Pathol Transl Med 2016; 50(6): 411.
[21]
Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comput Chem 2010; 31(2): 455.
[22]
Ionescu-Tucker A, Cotman CW. Emerging roles of oxidative stress in brain aging and Alzheimer’s disease. Neurobiol Aging 2021; 107: 86-95.
[http://dx.doi.org/10.1016/j.neurobiolaging.2021.07.014] [PMID: 34416493]
[23]
Ren P, Xiao B, Wang LP, Li YS, Jin H, Jin QH. Nitric oxide impairs spatial learning and memory in a rat model of Alzheimer’s disease via disturbance of glutamate response in the hippocampal dentate gyrus during spatial learning. Behav Brain Res 2022; 422: 113750.
[http://dx.doi.org/10.1016/j.bbr.2022.113750] [PMID: 35033612]
[24]
Amanollahi M, Jameie M, Heidari A, Rezaei N. The dialogue between neuroinflammation and adult neurogenesis: Mechanisms involved and alterations in neurological diseases. Mol Neurobiol 2022; 60(2): 923-59. https://link.springer.com/article/10.1007/s12035-022-03102-z
[25]
Kempermann G, Song H, Gage FH. Neurogenesis in the adult hippocampus. Cold Spring Harb Perspect Biol 2015; 7(9): a018812.
[http://dx.doi.org/10.1101/cshperspect.a018812] [PMID: 26330519]
[26]
Tong XK, Royea J, Hamel E. Simvastatin rescues memory and granule cell maturation through the Wnt/β-catenin signaling pathway in a mouse model of Alzheimer’s disease. Cell Death Dis 2022; 13(4): 325.
[http://dx.doi.org/10.1038/s41419-022-04784-y] [PMID: 35397630]
[27]
Wiatrak B, Kubis-Kubiak A, Piwowar A, Barg E. PC12 Cell Line: Cell types, coating of culture vessels, differentiation and other culture conditions. Cells 2020; 9(4): 958.
[http://dx.doi.org/10.3390/cells9040958] [PMID: 32295099]
[28]
Melzer D, Galloway T. Bisphenol A and adult disease: Making sense of fragmentary data and competing inferences. Ann Intern Med 2011; 155(6): 392-4.
[http://dx.doi.org/10.7326/0003-4819-155-6-201109200-00009] [PMID: 21930858]
[29]
Ni Y, Hu L, Yang S, et al. Bisphenol A impairs cognitive function and 5-HT metabolism in adult male mice by modulating the microbiota-gut-brain axis. Chemosphere 2021; 282: 130952.
[http://dx.doi.org/10.1016/j.chemosphere.2021.130952] [PMID: 34082316]
[30]
Bi N, Ding J, Zou R, Gu X, Liu ZH, Wang HL. Developmental exposure of bisphenol A induces spatial memory deficits by weakening the excitatory neural circuits of CA3-CA1 and EC-CA1 in mice. Toxicol Appl Pharmacol 2021; 426: 115641.
[http://dx.doi.org/10.1016/j.taap.2021.115641] [PMID: 34242568]
[31]
Gu YX, Liang XX, Yin NY, et al. New insights into mechanism of bisphenol analogue neurotoxicity: Implications of inhibition of O-GlcNAcase activity in PC12 cells. Arch Toxicol 2019; 93(9): 2661-71.
[http://dx.doi.org/10.1007/s00204-019-02525-3] [PMID: 31332466]
[32]
Zhang Y, Li S, Wu J, et al. The orphan nuclear receptor Nur77 plays a vital role in BPA-induced PC12 cell apoptosis. Ecotoxicol Environ Saf 2021; 213: 112026.
[http://dx.doi.org/10.1016/j.ecoenv.2021.112026] [PMID: 33582411]
[33]
Ayazgök B, Tüylü Küçükkılınç T. Low‐dose bisphenol A induces RIPK1‐mediated necroptosis in SH‐SY5Y cells: Effects on TNF‐α and acetylcholinesterase. J Biochem Mol Toxicol 2019; 33(1): e22233.
[http://dx.doi.org/10.1002/jbt.22233] [PMID: 30238673]
[34]
Kobayashi Y, Oguro A, Yagi E, Mitani A, Kudoh SN, Imaoka S. Bisphenol A and rotenone induce S-nitrosylation of protein disulfide isomerase (PDI) and inhibit neurite outgrowth of primary cultured cells of the rat hippocampus and PC12 cells. J Toxicol Sci 2020; 45(12): 783-94.
[http://dx.doi.org/10.2131/jts.45.783] [PMID: 33268678]
[35]
Moreira P, Honda K, Liu Q, et al. Oxidative stress: The old enemy in Alzheimer’s disease pathophysiology. Curr Alzheimer Res 2005; 2(4): 403-8.
[http://dx.doi.org/10.2174/156720505774330537] [PMID: 16248845]
[36]
Aslan M, Ozben T. Reactive oxygen and nitrogen species in Alzheimer’s disease. Curr Alzheimer Res 2004; 1(2): 111-9.
[http://dx.doi.org/10.2174/1567205043332162] [PMID: 15975075]
[37]
Hamid M, Mansoor S, Amber S, Zahid S. A quantitative meta-analysis of vitamin C in the pathophysiology of Alzheimer’s disease. Front Aging Neurosci 2022; 14: 970263.
[http://dx.doi.org/10.3389/fnagi.2022.970263] [PMID: 36158537]
[38]
Kobayashi K, Liu Y, Ichikawa H, Takemura S, Minamiyama Y. Effects of bisphenol a on oxidative stress in the rat brain. Antioxidants 2020; 9(3)
[http://dx.doi.org/10.3390/antiox9030240]
[39]
Solleiro-Villavicencio H, Rivas-Arancibia S. Effect of chronic oxidative stress on neuroinflammatory response mediated by cd4+t cells in neurodegenerative diseases. Front Cell Neurosci 2018; 144.
[40]
Siciliano R, Barone E, Calabrese V, Rispoli V, Allan Butterfield D, Mancuso C. Experimental research on nitric oxide and the therapy of Alzheimer disease: A challenging bridge. CNS Neurol Disord Drug Targets 2011; 10(7): 766-76.
[http://dx.doi.org/10.2174/187152711798072356] [PMID: 21999733]
[41]
Singh SA, Suresh S, Singh A, Chandran L, Vellapandian C. Perspectives of ozone induced neuropathology and memory decline in Alzheimer’s disease: A systematic review of preclinical evidences. Environ Pollut 2022; 313: 120136.
[http://dx.doi.org/10.1016/j.envpol.2022.120136] [PMID: 36089140]
[42]
Singh SA, Suresh S, Vellapandian C. Ozone-induced neurotoxicity: In vitro and in vivo evidence. Ageing Res Rev 2023; 91: 102045.
[http://dx.doi.org/10.1016/j.arr.2023.102045] [PMID: 37652313]
[43]
Ohira K. Regulation of Adult Neurogenesis in the Cerebral Cortex. J Neurol Neuromedicine 2018; 3(4): 59-64.
[http://dx.doi.org/10.29245/2572.942X/2018/4.1192]
[44]
Carreira BP, Santos DF, Santos AI, Carvalho CM, Araujo IM. Nitric oxide regulates neurogenesis in the hippocampus following seizures. Oxid Med Cell Longev 2015; 451512.
[http://dx.doi.org/10.1155/2015/451512]
[45]
Shohayeb B, Diab M, Ahmed M, Ng DCH. Factors that influence adult neurogenesis as potential therapy. Transl Neurodegener 2018; 7(1): 4.
[http://dx.doi.org/10.1186/s40035-018-0109-9] [PMID: 29484176]
[46]
Rubio-Perez JM, Morillas-Ruiz JM A. A Review: Inflammatory process in alzheimer’s disease. Role of Cytokines Sci World J 2012.
[47]
Bassani TB, Bonato JM, Machado MMF, et al. Decrease in adult neurogenesis and neuroinflammation are involved in spatial memory impairment in the streptozotocin-induced model of sporadic alzheimer’s disease in rats. Mol Neurobiol 2018; 55(5): 4280-96. [Internet].
[PMID: 28623617]
[48]
Arredondo SB, Valenzuela-Bezanilla D, Mardones MD, Varela-Nallar L. Role of Wnt signaling in adult hippocampal neurogenesis in health and disease. Front Cell Dev Biol 2020; 8: 860.
[http://dx.doi.org/10.3389/fcell.2020.00860] [PMID: 33042988]
[49]
Davis EK, Zou Y, Ghosh A. Wnts acting through canonical and noncanonical signaling pathways exert opposite effects on hippocampal synapse formation. Neural Dev 2008; 3(1): 32.
[http://dx.doi.org/10.1186/1749-8104-3-32] [PMID: 18986540]
[50]
Pal D, Mukherjee S, Song IH, Nimse SB. GSK-3 Inhibitors: A new class of drugs for alzheimer’s disease treatment. Curr Drug Targets 2021; 22(15): 1725-37.
[http://dx.doi.org/10.2174/1389450122666210114095307] [PMID: 33459229]
[51]
Wang Q, Huang X, Su Y, et al. Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease. Brain 2022; 145(12): 4474-88.https://pubmed.ncbi.nlm.nih.gov/35788280/
[http://dx.doi.org/10.1093/brain/awac236] [PMID: 35788280]
[52]
Ferrari G, Avila M, Medina M, Perez-Palma E, Bustos B, Alarcon M. Wnt/β-catenin signaling in Alzheimer’s disease. CNS Neurol Disord Drug Targets 2014; 13(5): 745-54.
[http://dx.doi.org/10.2174/1871527312666131223113900] [PMID: 24365184]
[53]
da Cruz AB, Silva O, Gabriela Henriques A, Catarina TSDS, da Cruz F, Silva E. Wnt signalling is a relevant pathway contributing to amyloid beta-peptide-mediated neuropathology in alzheimers disease. CNS Neurol Disord Drug Targets 2012; 9(6): 720-6.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy