Neurotoxic Effect of Flavonol Myricetin in the Presence of Excess Copper

Abstract

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.

Beneficial Effects of Laurel (Laurus nobilis L.) and Myrtle (Myrtus communis L.) Extract on Rat Health

“…In Myrtle extract, the main polyphenolic components are Myricetin-3-O-rham (36.68%), Myricetin-3-O-gallac (33.20%), Miricetin (14.48%) and 5-O-galloyl quinic Acid (7.96%). Myricetin can act as an antioxidant and as pro-oxidant, possesses six hydroxyl groups and thus has great potential for participating in oxidation and redox cycling as described in [39]. Its potential to act as a pro-oxidant due to its tendency to undergo autoxidation depending upon its environment resulting in changes in SOD and CAT activity.…”

“…Biomarkers for lipid peroxidation (MDA) in tissues were determined by measuring the content of TBARS using a method described by our previous paper [38,39]. Briefly, after centrifugation supernatant of the homogenized tissue (200 µL) was mixed with 200 µL of 8.1% sodium dodecyl sulphate (SDS), 1.5 mL of 20% acetic acid (pH = 3.5), and 1.5 mL of 0.81% thiobarbituric acid, and incubated at 95 • C for 60 min.…”

Anti-Oxidative, Anti-Inflammatory and Anti-Apoptotic Effects of Flavonols: Targeting Nrf2, NF-κB and p53 Pathways in Neurodegeneration

“…However, the full potential of flavonoids in neuroprotection is far from closure. It is known that in the presence of transient metals such as copper and iron, flavonoids may act as pro-oxidants and contribute to increases in ROS, intensifying OS and threatening neuronal viability [123,196,197]. Moreover, flavonoids are metabolically altered in the gut after oral consumption.…”

“…Finally, it should be mentioned that, in certain circumstances, myricetin, similar to quercetin, may exert a neurotoxic effect when applied together with excess copper. In SH-SY5Y cells, myricetin promoted the production of ROS and caspase-independent cell death without affecting p53 expression and its target Bax [197]. Hence, the adverse effects of quercetin, myricetin and potentially some other flavonols should not be neglected.…”

Investigation of the pharmacological potential of myricetin on alcohol addiction in mice

“…Alcohol addiction, like different substance addictions, causes alcohol-seeking (craving) and maintenance of alcohol use, involving multiple neurotransmitter systems such as dopamine, glutamate, γaminobutyric acid (GABA), serotonin, and peroxisome proliferator-activated receptors (PPARs) system [10]. The publications review indicates that myricetin was demonstrated to affect the glutaminergic system, GABAergic system, peroxisome proliferator-activated receptors (PPARs) [11][12][13][14][15][16]. For example, an earlier investigation demonstrated that NMDA receptor antagonists reduced the development of ethanol-CPP [17][18][19].…”