Curcumin attenuates paraquat-induced cell death in human neuroblastoma cells through modulating oxidative stress and autophagy

Highlights

• Curcumin attenuated APP accumulation in the paraquat-induced SH-SY5Ycells.

• Curcumin alleviated paraquat-induced SH-SY5Y cell death and suppressed excess ROS production.

• Curcumin enhanced autophagy and rescued chloroquine-treated SH-SY5Y cells.

Abstract

Paraquat is a neurotoxic agent, and oxidative stress plays an important role in neuronal cell death after paraquat exposure. In this study, we assessed the neuroprotective effect of curcumin against paraquat and explored the underlying mechanisms of curcumin in vitro. Curcumin treatment prevented paraquat-induced reactive oxygen species (ROS) and apoptotic cell death. Curcumin also exerted a neuroprotective effect by increasing the expression of anti-apoptotic and antioxidant genes. The pretreatment of curcumin significantly decreased gene expression and protein production of amyloid precursor protein. The activation of autophagy process was found defective in paraquat-induced cells, indicated by the accumulation and reduction of LC3I/II. Noteworthy, curcumin restored LC3I/II expression after the pretreatment. Collectively, curcumin demonstrated as a prominent suppressor of ROS, and could reverse autophagy induction in SH-SY5Y cells. The consequences of this were the reduction of APP production and prevention of SH-SY5Y cells from apoptosis. Altogether, curcumin potentially serves as a therapeutic agent of neurodegenerative diseases, associated with ROS overproduction and autophagy dysfunction.

Introduction

Alzheimeŕs disease (AD) pathology is characterized by the accumulation of extracellular plaques, including aggregated amyloid-β (Aβ) peptide, and intracellular tangles in the brain. Genetic evidence implicates deregulated Aβ homeostasis as an early event of AD pathology [29]. For this reason, most AD therapies have targeted at Aβ production. Autophagy is involved in the intracellular turnover of proteins and cell organelles and has a key role in regulating cell fates in response to stress [22], [25]. Alteration of endocytic pathway can impede turnover of autophagic vacuoles and lead to diseases [33]. The modulation of autophagy was highlighted as a sophisticated mechanism in AD, since the induction and activation of autophagy can promote Aβ degradation and consequently reduce AD pathology [37]. Disrupted autophagy would lead to the accumulation of intracellular proteins, and the aberration of the lysosomal pathway might lead to neurodegeneration. Reportedly, the impaired clearance of autophagic vacuoles was observed in AD animal models and also AD patients [4], [24].

Nowadays, therapies of AD patients are mostly palliative cares and rarely improve the disease symptoms. For this reason, the AD aetiology is attracted scientist attentions to investigate the causative molecular mechanisms of the disease, and develop novel therapeutic options. Curcumin is a naturally-occurring polyphenolic compound, extracted from turmeric, the powered rhizome of the plant Curcuma longa. Curcumin comprises 3 to 5% of turmeric and functions as pharmacologically active component [40]. Several in vitro, animal and human studies demonstrated potent antioxidant and anti-inflammatory properties of curcuminoids [3], [6], [32], [38]. The ability of curcumin to reduce Aβ production, inflammation, and oxidative stress highlights its potential use for AD treatment.

In the present study, the exposure of SH-SY5Y cells to paraquat resulted in the increase of APP production/accumulation, exerted oxidative stress, and eventually led to cell death. Curcumin exhibited the protective roles on paraquat-induced neurotoxicity and its mechanisms of action involved in the activation of autophagy in human neuroblastoma SH-SY5Y cells.