A Novel Tetramethylpyrazine Derivative Protects Against Glutamate-Induced Cytotoxicity Through PGC1α/Nrf2 and PI3K/Akt Signaling Pathways.

Haiyun Chen,Yuqiang Wang,Jie Cao,Yewei Sun,Luchen Shan,Zaijun Zhang,Gaoxiao Zhang,Zeyu Zhu,Pei Yu

doi:10.3389/fnins.2018.00567

Abstract

Glutamate-induced excitotoxicity is one of the main causes of neuronal cell death in stroke. Compound 22a has been previously reported as a promising neuroprotective compound derived from tetramethylpyrazine, which is a widely used active ingredient of traditional Chinese medicine Chuanxiong (Ligusticum wallichii Franchat). Compound 22a can protect neurons from oxidative stress-induced PC12 cell death and alleviates the infarct areas and brain edema in a rat permanent middle cerebral artery occlusion model. In the current work, we further investigated the neuroprotective effects and underlying mechanisms of compound 22a against glutamate-induced excitotoxicity in primary culture of rat cerebellar granule neurons (CGNs). We found that pretreatment with compound 22a prevented glutamate-induced neuronal damage by maintaining mitochondrial membrane potential and attenuating cellular apoptosis. Compound 22a could also enhance peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) transcriptional activity and induce nuclear accumulation of Nrf2 in PC12 cells. Accordingly, pretreatment with compound 22a reversed the glutamate-induced down-regulation of expression of the proteins PGC1α, transcriptional factor NF-E2-related factor 2 (Nrf2), and hemooxygenase 1 (HO-1). In addition, compound 22a increased the phosphorylation of phosphoinositide 3-kinase (p-PI3K), phosphorylated protein kinase B (p-Akt), and glycogen synthase kinase 3β (p-GSK3β). Meanwhile, the small interfering RNA-mediated silencing of PGC1α expression and selective inhibitors targeting PI3K/Akt (LY294002 and Akt-iv) could significantly attenuate the neuroprotective effect of compound 22a. Taken together, compound 22a protected against glutamate-induced CGN injury possibly in part through regulation of PGC1α/Nrf2 and PI3K/Akt pathways.

Highlights

Ischemic stroke is one of the major causes of human death and disability worldwide (Donnan et al, 2008)
We reported that compound 22a exhibited neuroprotective effects against oxidative stress-induced neuronal loss in vitro and protected against ischemic stroke in vivo (Chen et al, 2017)
The neuroprotective effects of compound 22a against glutamate-induced excitotoxicity were investigated in the current study

Summary

Introduction

Ischemic stroke is one of the major causes of human death and disability worldwide (Donnan et al, 2008). Glutamate-induced excitotoxicity has been demonstrated to be involved in neuronal cell death in stroke (Lai et al, 2014). Overproduction of extracellular glutamate leads to uncontrolled, continuous depolarization of neurons in a toxic process called excitotoxicity. Glutamateinduced excitotoxicity is associated with the over-stimulation of glutamate receptors, inducing the impairment of intracellular Ca2+ homeostasis and subsequently leading to overproduction of free radicals, overactivation of proteases and kinases, etc. Stimulation of the PI3K/Akt pathway is neuroprotective against hypoxic and excitotoxic neuronal death in vitro and ischemic neuronal death in vivo, and there is increasingly evidence to indicate cross talk between the Nrf and PI3K/Akt pathways in response to glutamate caused cell injury (Jo et al, 2012; Lee et al, 2015)

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Results

Conclusion