Ginsenoside Re Inhibits ROS/ASK-1 Dependent Mitochondrial Apoptosis Pathway and Activation of Nrf2-Antioxidant Response in Beta-Amyloid-Challenged SH-SY5Y Cells.

Meichen Liu,Juhui Qiao,Ying Liu,Jiawen Wang,Siming Wang,Shiting Yu,Xueyuan Bai,Wenxue Zhao,Daqing Zhao

doi:10.3390/molecules24152687

Meichen Liu, Juhui Qiao + Show 7 more

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https://doi.org/10.3390/molecules24152687

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Abstract

Accumulation of amyloid-β (Aβ), which results in the formation of senile plaques that cause oxidative damage and neuronal cell death, has been accepted as the major pathological mechanism of Alzheimer’s disease (AD). Hence, inhibition of Aβ-induced oxidative damage and neuronal cell apoptosis represents the effective strategies in combating AD. Ginsenoside Re (Re) has pharmacological effects against Aβ-induced neurotoxicity. However, its molecular mechanism remains elusive. The present study evaluated the effect of Re against Aβ-induced cytotoxicity and apoptosis in SH-SY5Y cells, and investigated the underlying mechanism. We demonstrate that Re inhibits the Aβ-triggered mitochondrial apoptotic pathway, as indicated by maintenance of mitochondrial functional, elevated Bcl-2/Bax ratio, reduced cytochrome c release, and inactivation of caspase-3/9. Re attenuated Aβ-evoked reactive oxygen species (ROS) production, apoptosis signal-regulating kinase 1 (ASK1) phosphorylation, and JNK activation. ROS-scavenging abrogated the ability of Re to alter ASK-1 activation. Simultaneously, inhibition of JNK abolished Re-induced Bax downregulation in Aβ-challenged SH-SY5Y cells. In addition, Re enhanced activation of the nuclear factor-E2-related factor 2 (Nrf2) in Aβ-induced SH-SY5Y cells. Knockdown of Nrf2 by small interfering RNA targeting Nrf2 abolished the protective effect of Re. Our findings indicate that Re could be a potential therapeutic approach for the treatment of AD.

Highlights

Alzheimer’s disease (AD), which affects millions of older adults worldwide, is the most prevalent chronic neurodegenerative disorder [1]
In the range (20, 25, and 30 uM), ginsenoside Re has a promotive effect on neuronal cell survival. 25 μM ginsenoside Re reached a peak with a 43.51% increase compared with Aβ-induced alone
Ginsenoside Re significantly reduced Aβ-induced increases in caspase-3/7 activity and decreases in caspase-9 activity, but did not significantly affect caspase-8 or caspase-12 activities (Figure 1e,f). These results suggest that the mitochondrial pathway, rather than the endoplasmic reticulum or death receptor pathway, contributes to the neuroprotective effect of ginsenoside Re

Summary

Introduction

Alzheimer’s disease (AD), which affects millions of older adults worldwide, is the most prevalent chronic neurodegenerative disorder [1]. The number of patients with AD is rapidly increasing such that by 2050, the number of individuals with AD will exceed 130 million worldwide [2]. Increased β-amyloid (Aβ) plaques in the brain are regarded as the pathological hallmark of AD [3]. The self-assembling of Aβ into neurotoxic aggregates is considered a central event in the pathogenesis of AD (amyloid hypothesis). Several adverse factors are known to contribute to Aβ aggregation. Current research indicates that abnormal interactions with model membranes have been evidenced to foster

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