Quercetin Protects against Okadaic Acid-Induced Injury via MAPK and PI3K/Akt/GSK3β Signaling Pathways in HT22 Hippocampal Neurons

Wei Jiang; Tao Luo; Sheng Li; Yue Zhou; Xiu-Yin Shen; Feng He; Jie Xu; Hua-Qiao Wang

doi:10.1371/journal.pone.0152371

Quercetin Protects against Okadaic Acid-Induced Injury via MAPK and PI3K/Akt/GSK3β Signaling Pathways in HT22 Hippocampal Neurons

PLoS One. 2016 Apr 6;11(4):e0152371. doi: 10.1371/journal.pone.0152371. eCollection 2016.

Authors

Wei Jiang^{1

2}, Tao Luo¹, Sheng Li¹, Yue Zhou¹, Xiu-Yin Shen¹, Feng He³, Jie Xu¹, Hua-Qiao Wang¹

Affiliations

¹ Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
² Department of Anatomy and Histoembryology, Zhaoqing Medical College, Zhaoqing, Guangdong, 526020, China.
³ School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China.

Abstract

Increasing evidence shows that oxidative stress and the hyperphosphorylation of tau protein play essential roles in the progression of Alzheimer's disease (AD). Quercetin is a major flavonoid that has anti-oxidant, anti-cancer and anti-inflammatory properties. We investigated the neuroprotective effects of quercetin to HT22 cells (a cell line from mouse hippocampal neurons). We found that Okadaic acid (OA) induced the hyperphosphorylation of tau protein at Ser199, Ser396, Thr205, and Thr231 and produced oxidative stress to the HT22 cells. The oxidative stress suppressed the cell viability and decreased the levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), mitochondria membrane potential (MMP) and Glutathione peroxidase (GSH-Px). It up-regulated malondialdehyde (MDA) production and intracellular reactive oxygen species (ROS). In addition, phosphoinositide 3 kinase/protein kinase B/Glycogen synthase kinase3β (PI3K/Akt/GSK3β) and mitogen activated protein kinase (MAPK) were also involved in this process. We found that pre-treatment with quercetin can inhibited OA-induced the hyperphosphorylation of tau protein and oxidative stress. Moreover, pre-treatment with quercetin not only inhibited OA-induced apoptosis via the reduction of Bax, and up-regulation of cleaved caspase 3, but also via the inhibition of PI3K/Akt/GSK3β, MAPKs and activation of NF-κB p65. Our findings suggest the therapeutic potential of quercetin to treat AD.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Glutathione Peroxidase / metabolism
Glycogen Synthase Kinase 3 / metabolism*
Glycogen Synthase Kinase 3 beta
Hippocampus / cytology
Hippocampus / drug effects*
Hippocampus / enzymology
MAP Kinase Signaling System*
Mice
Neurons / drug effects*
Neurons / enzymology
Okadaic Acid / toxicity*
Phosphatidylinositol 3-Kinases / metabolism*
Phosphorylation
Proto-Oncogene Proteins c-akt / metabolism*
Quercetin / pharmacology*
Reactive Oxygen Species / metabolism
Superoxide Dismutase / metabolism
tau Proteins / metabolism

Substances

Reactive Oxygen Species
tau Proteins
Okadaic Acid
Quercetin
Glutathione Peroxidase
Superoxide Dismutase
Phosphatidylinositol 3-Kinases
Glycogen Synthase Kinase 3 beta
Gsk3b protein, mouse
Proto-Oncogene Proteins c-akt
Glycogen Synthase Kinase 3

Grants and funding

This work was supported by National Key Development Program for Basic Research of China (No. 2006cb500700), Science and Technology Innovation Project of Guangdong Education Department (No.2012KJCX0089), Medical Scientific Research Foundation of Guangdong Province (No. A2010222, A2015032), Fundamental Research Founds for the Central Universities of China (No. 14ykpy03), National Natural Science Foundation of China (No.81173577, 81501093), Natural Science Foundation of Guangdong Province (No.2015A030313066, 2015A030310251), and Science and Technology Planning Project of Guangdong Province (No.2014A020212622).