Methyl lucidone exhibits neuroprotective effects on glutamate-induced oxidative stress in HT-22 cells via Nrf-2/HO-1 signaling

Jee-Yun Park,Yoon-Sil Yang,Yanji Cui,Jinji Wu,Khulan Amarsanaa,Ji-Hyung Lee,Sung-Cherl Jung,Su-Yong Eun

doi:10.1186/s13765-019-0474-9

Abstract

Oxidative stress causes neuronal cell death in various neurodegenerative diseases, such as Alzheimer’s disease, ischemia, and Parkinson’s disease. Therefore, reducing intracellular reactive oxygen species (ROS) has been evaluated as an effective treatment strategy for neurodegenerative disorders. Methyl lucidone (MLC) extracted from Lindera erythrocarpa Makino (Lauraceae) has been previously reported to exhibit microglial-mediated neuroprotective effects via inhibiting neuroinflammation. However, the antioxidant effects of MLC are still unclear. The aim of this study was to determine the neuroprotective mechanism of MLC in HT-22 neurons against oxidative stress induced by glutamate. In results, the pretreatment of MLC significantly enhanced the viability of HT-22 cells under glutamate-induced oxidative conditions, suggesting that MLC has a neuronal mechanism to protect neurons without microglial regulation. Also, the glutamate effect to increase ROS production was effectively blocked by MLC without any free radical scavenging activity. To induce this antioxidant effect, MLC upregulated the expression of heme oxygenase 1 (HO-1) and nuclear translocation of nuclear factor-E2-related factor 2 (Nrf-2), known as an intracellular antioxidant enzyme, and its transcription factor. Additionally, Akt phosphorylation regulating Nrf-2 was confirmed to be involved in the neuroprotective signaling activated by MLC. These results indicate that MLC may play a role as an antioxidant agent to inhibit neurodegenerative processes via activating antioxidant signaling pathways that include Nrf-2 and phosphatidylinositol 3-kinase (PI3K).

Highlights

Neurotoxicity in glutamatergic neurons is the major cause to induce cell death in neurodegenerative diseases, such as Alzheimer’s disease, ischemia, and Parkinson’s disease [1,2,3]
The results showed that Methyl lucidone (MLC) preserved the survival of HT-22 cells under glutamate-induced oxidative conditions via activating the heme oxygenase 1 (HO-1) antioxidant enzyme and that the activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling was required for the antioxidant effect
The effect of MLC to reduce reactive oxygen species (ROS) production was partially but significantly blocked by the addition of SnPP (Glu + MLC: 104.8 ± 2.8, Glu + MLC + SnPP: 125.3 ± 3.4%, p < 0.05, compared with Glu + MLC). These results indicate that the Nuclear factor-E2-related factor-2 (Nrf-2)/HO-1 signaling pathway may participate in the antioxidant signaling pathway that is activated by MLC

Summary

Introduction

Neurotoxicity in glutamatergic neurons is the major cause to induce cell death in neurodegenerative diseases, such as Alzheimer’s disease, ischemia, and Parkinson’s disease [1,2,3]. To moderate oxidative damage and maintain cellular redox homeostasis, many types of mammalian cells possess a variety of antioxidant systems [5]. One of the important intracellular enzymes for antioxidant signaling is heme oxygenase 1 (HO-1). Nuclear factor-E2-related factor-2 (Nrf-2) regulates the expression of genes encoding phase ΙΙ detoxification enzymes and antioxidants, including HO-1 [6]. Because Nrf-2 is negatively regulated by Kelch-like ECH-associated protein (Keap1) and Nrf-2 phosphorylation is required for its dissociation from Keap, various kinases, such as phosphatidylinositol 3-kinase (PI3K), participate in the HO-1-mediated antioxidant signaling pathway [7, 8]

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