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Article

Neurotoxic Effect of Flavonol Myricetin in the Presence of Excess Copper

1
Division of Physical Chemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia
2
Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
3
Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
4
Department of Psychology, Catholic University of Croatia, 10000 Zagreb, Croatia
5
King’s College London, London WC2R 2LS, UK
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Luciana Mosca
Molecules 2021, 26(4), 845; https://doi.org/10.3390/molecules26040845
Received: 15 January 2021 / Revised: 1 February 2021 / Accepted: 3 February 2021 / Published: 5 February 2021
Oxidative stress (OS) induced by the disturbed homeostasis of metal ions is one of the pivotal factors contributing to neurodegeneration. The aim of the present study was to investigate the effects of flavonoid myricetin on copper-induced toxicity in neuroblastoma SH-SY5Y cells. As determined by the MTT method, trypan blue exclusion assay and measurement of ATP production, myricetin heightened the toxic effects of copper and exacerbated cell death. It also increased copper-induced generation of reactive oxygen species, indicating the prooxidative nature of its action. Furthermore, myricetin provoked chromatin condensation and loss of membrane integrity without caspase-3 activation, suggesting the activation of both caspase-independent programmed cell death and necrosis. At the protein level, myricetin-induced upregulation of PARP-1 and decreased expression of Bcl-2, whereas copper-induced changes in the expression of p53, p73, Bax and NME1 were not further affected by myricetin. Inhibitors of ERK1/2 and JNK kinases, protein kinase A and L-type calcium channels exacerbated the toxic effects of myricetin, indicating the involvement of intracellular signaling pathways in cell death. We also employed atomic force microscopy (AFM) to evaluate the morphological and mechanical properties of SH-SY5Y cells at the nanoscale. Consistent with the cellular and molecular methods, this biophysical approach also revealed a myricetin-induced increase in cell surface roughness and reduced elasticity. Taken together, we demonstrated the adverse effects of myricetin, pointing out that caution is required when considering powerful antioxidants for adjuvant therapy in copper-related neurodegeneration. View Full-Text
Keywords: myricetin; prooxidative activity; copper toxicity; atomic force microscopy; elasticity; roughness myricetin; prooxidative activity; copper toxicity; atomic force microscopy; elasticity; roughness
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MDPI and ACS Style

Sadžak, A.; Vlašić, I.; Kiralj, Z.; Batarelo, M.; Oršolić, N.; Jazvinšćak Jembrek, M.; Kušen, I.; Šegota, S. Neurotoxic Effect of Flavonol Myricetin in the Presence of Excess Copper. Molecules 2021, 26, 845. https://doi.org/10.3390/molecules26040845

AMA Style

Sadžak A, Vlašić I, Kiralj Z, Batarelo M, Oršolić N, Jazvinšćak Jembrek M, Kušen I, Šegota S. Neurotoxic Effect of Flavonol Myricetin in the Presence of Excess Copper. Molecules. 2021; 26(4):845. https://doi.org/10.3390/molecules26040845

Chicago/Turabian Style

Sadžak, Anja, Ignacija Vlašić, Zoran Kiralj, Marijana Batarelo, Nada Oršolić, Maja Jazvinšćak Jembrek, Ines Kušen, and Suzana Šegota. 2021. "Neurotoxic Effect of Flavonol Myricetin in the Presence of Excess Copper" Molecules 26, no. 4: 845. https://doi.org/10.3390/molecules26040845

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