FA-97, a New Synthetic Caffeic Acid Phenethyl Ester Derivative, Protects against Oxidative Stress-Mediated Neuronal Cell Apoptosis and Scopolamine-Induced Cognitive Impairment by Activating Nrf2/HO-1 Signaling

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Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disorder with cognitive deficits, which is becoming markedly more common in the world. Currently, the exact cause of AD is still unclear, and no curative therapy is available for preventing or mitigating the disease progression. Caffeic acid phenethyl ester (CAPE), a natural phenolic compound derived from honeybee hive propolis, has been reported as a potential therapeutic agent against AD, while its application is limited due to the low water solubility and poor bioavailability. Here, caffeic acid phenethyl ester 4- O-glucoside (FA-97) is synthesized. We validate that FA-97 attenuates H ₂O ₂-induced apoptosis in SH-SY5Y and PC12 cells and suppresses H ₂O ₂-induced oxidative stress by inhibiting the ROS level, malondialdehyde (MDA) level, and protein carbonylation level, as well as induces cellular glutathione (GSH) and superoxide dismutase (SOD). Mechanistically, FA-97 promotes the nuclear translocation and transcriptional activity of Nrf2 associated with the upregulated expression of HO-1 and NQO-1. The prime importance of Nrf2 activation in the neuroprotective and antioxidant effects of FA-97 is verified by Nrf2 siRNA transfection. In addition, FA-97 prevents scopolamine- (SCOP-) induced learning and memory impairments in vivo via reducing neuronal apoptosis and protecting against cholinergic system dysfunction in the hippocampus and cortex. Moreover, the increased MDA level and low total antioxidant capacity in SCOP-treated mouse brains are reversed by FA-97, with the increased expression of HO-1, NQO-1, and nuclear Nrf2. In conclusion, FA-97 protects against oxidative stress-mediated neuronal cell apoptosis and SCOP-induced cognitive impairment by activating Nrf2/HO-1 signaling, which might be developed as a therapeutic drug for AD.

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Most cited references 36

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Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region.

P Moi, K. Chan, I Asunis … (1994)

Hypersensitive site 2 located in the beta-globin locus control region confers high levels of expression to the genes of the beta-globin cluster. A tandem repeat of the consensus sequence for the transcription factors AP1 and NF-E2 (activating protein 1 and nuclear factor erythroid 2, respectively) is present within hypersensitive site 2 and is absolutely required for strong enhancer activity. This sequence binds, in vitro and in vivo, to ubiquitous proteins of the AP1 family and to the recently cloned erythroid-specific transcription factor NF-E2. Using the tandem repeat as a recognition site probe to screen a lambda gt11 cDNA expression library from K562 cells, we isolated several DNA binding proteins. Here, we report the characterization of one of the clones isolated. The gene, which we named Nrf2 (NF-E2-related factor 2), is encoded within a 2.2-kb transcript and predicts a 66-kDa protein with a basic leucine zipper DNA binding domain highly homologous to that of NF-E2. Although Nrf2 is expressed ubiquitously, a role of this protein in mediating enhancer activity of hypersensitive site 2 in erythroid cells cannot be excluded. In this respect, Nrf2 contains a powerful acidic activation domain that may participate in the transcriptional stimulation of beta-globin genes.

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Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson's disease and Alzheimer's disease.

Tianfang Jiang, Qian Sun, Shengdi Chen (2016)

Oxidative stress reflects an imbalance between the overproduction and incorporation of free radicals and the dynamic ability of a biosystem to detoxify reactive intermediates. Free radicals produced by oxidative stress are one of the common features in several experimental models of diseases. Free radicals affect both the structure and function of neural cells, and contribute to a wide range of neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Although the precise mechanisms that result in the degeneration of neurons and the relevant pathological changes remain unclear, the crucial role of oxidative stress in the pathogenesis of neurodegenerative diseases is associated with several proteins (such as α-synuclein, DJ-1, Amyloid β and tau protein) and some signaling pathways (such as extracellular regulated protein kinases, phosphoinositide 3-kinase/Protein Kinase B pathway and extracellular signal-regulated kinases 1/2) that are tightly associated with the neural damage. In this review, we present evidence, gathered over the last decade, concerning a variety of pathogenic proteins, their important signaling pathways and pathogenic mechanisms associated with oxidative stress in Parkinson's disease and Alzheimer's disease. Proper control and regulation of these proteins' functions and the related signaling pathways may be a promising therapeutic approach to the patients. We also emphasizes antioxidative options, including some new neuroprotective agents that eliminate excess reactive oxygen species efficiently and have a certain therapeutic effect; however, controversy surrounds some of them in terms of the dose and length of therapy. These agents require further investigation by clinical application in patients suffering Parkinson's disease and Alzheimer's disease.

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Natural Dietary Supplementation of Anthocyanins via PI3K/Akt/Nrf2/HO-1 Pathways Mitigate Oxidative Stress, Neurodegeneration, and Memory Impairment in a Mouse Model of Alzheimer’s Disease

Muhammad Ikram, Myeong Ok Kim, Tahir Ali … (2018)

Well-established studies have shown an elevated level of reactive oxygen species (ROS) that induces oxidative stress in the Alzheimer's disease (AD) patient's brain and an animal model of AD. Herein, we investigated the underlying anti-oxidant neuroprotective mechanism of natural dietary supplementation of anthocyanins extracted from Korean black beans in the amyloid precursor protein/presenilin-1 (APP/PS1) mouse model of AD. Both in vivo (APP/PS1 mice) and in vitro (mouse hippocampal HT22 cells) results demonstrated that anthocyanins regulate the phosphorylated-phosphatidylinositol 3-kinase-Akt-glycogen synthase kinase 3 beta (p-PI3K/Akt/GSK3β) pathways and consequently attenuate amyloid beta oligomer (AβO)-induced elevations in ROS level and oxidative stress via stimulating the master endogenous anti-oxidant system of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (Nrf2/HO-1) pathways and prevent apoptosis and neurodegeneration by suppressing the apoptotic and neurodegenerative markers such as activation of caspase-3 and PARP-1 expression as well as the TUNEL and Fluoro-Jade B-positive neuronal cells in the APP/PS1 mice. In vitro ApoTox-Glo™ Triplex assay results also showed that anthocyanins act as a potent anti-oxidant neuroprotective agent and reduce AβO-induced neurotoxicity in the HT22 cells via PI3K/Akt/Nrf2 signaling. Importantly, anthocyanins improve memory-related pre- and postsynaptic protein markers and memory functions in the APP/PS1 mice. In conclusion, our data suggested that consumption and supplementation of natural-derived anti-oxidant neuroprotective agent such as anthocyanins may be beneficial and suggest new dietary-supplement strategies for intervention in and prevention of progressive neurodegenerative diseases, such as AD.

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Author and article information

Contributors

Qi Wang:

ORCID: https://orcid.org/0000-0002-3389-8529

Yujie Huang:

ORCID: https://orcid.org/0000-0002-0197-3774

Journal

Journal ID (nlm-ta): Oxid Med Cell Longev

Journal ID (iso-abbrev): Oxid Med Cell Longev

Journal ID (publisher-id): OMCL

Title: Oxidative Medicine and Cellular Longevity

Publisher: Hindawi

ISSN (Print): 1942-0900

ISSN (Electronic): 1942-0994

Publication date Collection: 2019

Publication date (Electronic): 3 December 2019

Volume: 2019

Electronic Location Identifier: 8239642

Affiliations

¹Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China

²Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China

³Institute of Brain and Gut Axis (IBAG), Centre of Clinical Research for Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China

⁴Department of Chemistry, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China

⁵Clinical Medical College of Acupuncture Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China

Author notes

Academic Editor: Ana Cipak Gasparovic

Author information

Yi Luo https://orcid.org/0000-0001-8452-9523

Yu Mei https://orcid.org/0000-0001-7378-9880

Weirong Li https://orcid.org/0000-0002-3878-8724

Qi Wang https://orcid.org/0000-0002-3389-8529

Yujie Huang https://orcid.org/0000-0002-0197-3774

Article

DOI: 10.1155/2019/8239642

PMC ID: 6914945

PubMed ID: 31885818

SO-VID: c8885553-2e7a-4e8b-b98b-86d282c6c24e

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 3 July 2019

Date accepted : 30 August 2019

Funding

Funded by: Guangzhou University of Chinese Medicine

Award ID: A1-AFD018181Z3926

Funded by: Guangzhou Science Technology and Innovation Commission Technology Research Projects

Award ID: 201805010005

Award ID: 201803010047

Funded by: National Natural Science Foundation of China

Award ID: 81673627

Award ID: 81973918

Award ID: 81774199

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FA-97, a New Synthetic Caffeic Acid Phenethyl Ester Derivative, Protects against Oxidative Stress-Mediated Neuronal Cell Apoptosis and Scopolamine-Induced Cognitive Impairment by Activating Nrf2/HO-1 Signaling

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Most cited references 36

Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region.

Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson's disease and Alzheimer's disease.

Natural Dietary Supplementation of Anthocyanins via PI3K/Akt/Nrf2/HO-1 Pathways Mitigate Oxidative Stress, Neurodegeneration, and Memory Impairment in a Mouse Model of Alzheimer’s Disease

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