PI3K/Akt and ERK1/2 Signalling Are Involved in Quercetin-Mediated Neuroprotection against Copper-Induced Injury.

Klara Zubčić,Vedrana Radovanović,Goran Šimić,Maja Jazvinšćak Jembrek,Patrick R Hof,Nada Oršolić,Josipa Vlainić

doi:10.1155/2020/9834742

Abstract

Copper, a transition metal with essential cellular functions, exerts neurotoxic effects when present in excess by promoting production of reactive oxygen species (ROS). The aim of the present study was to investigate potential benefits of flavonoid quercetin against copper-induced toxicity. Results obtained with MTT assay indicate that the effects of quercetin are determined by the severity of the toxic insult. In moderately injured P19 neuronal cells, concomitant treatment with 150 μM quercetin improved viability by preventing ROS formation, caspase-3 activation, and chromatin condensation. Western blot analysis revealed that quercetin reduced copper-induced increase in p53 upregulated modulator of apoptosis (PUMA) expression and promoted upregulation of nucleoside diphosphate kinase NME1. Levels of p53 and Bax proteins were not affected by both copper and quercetin. UO126 and wortmannin, inhibitors of ERK1/2 and PI3K/Akt signalling pathways, respectively, prevented neuroprotective effects of quercetin. In severely injured neurons, 30 μM quercetin exerted strong prooxidative action and exacerbated cytotoxic effects of copper, whereas 150 μM quercetin failed to affect neuronal survival. These results demonstrate the dual nature of quercetin action in copper-related neurodegeneration. Hence, they are relevant in the context of considering quercetin as a possible therapeutic for neuroprotection and imply that detailed pharmacological and toxicological studies must be carried out for natural compounds capable of acting both as antioxidants and prooxidants.

Highlights

Neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’ disease, are chronic and progressive disorders characterized by slow degeneration of neurons and cell death
We investigated the effects of three different concentrations of quercetin (3, 30, and 150 μM) on copper-induced neuronal death
When quercetin was applied in the presence of 1 mM CuSO4, a decrease in neuronal survival was obtained with 30 μM quercetin, while treatment with 3 or 150 μM quercetin did not modify the effects of copper (Figure 2(b))

Summary

Introduction

Neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’ disease, are chronic and progressive disorders characterized by slow degeneration of neurons and cell death. Despite progress into the understanding of the complex network of molecular and cellular mechanisms that underlie the development of these devastating conditions, no effective pharmacological approaches are yet capable of delaying their onset and slowing down progression [2]. Compelling data suggest that oxidative stress is one of the pivotal factors contributing to the common pathophysiology of neurodegenerative diseases [3, 4]. Due to several reasons, including the presence of redox active transition metals, the brain is vulnerable to oxidative injury [5]. Copper is an essential transition metal required for catalytic activity of many brain proteins that are involved in various biological

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