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Memantine, NMDA Receptor Antagonist, Attenuates ox-LDL-Induced Inflammation and Oxidative Stress via Activation of BDNF/TrkB Signaling Pathway in HUVECs

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Abstract

Atherosclerosis is a chronic cardiovascular disease and contributes to pathogenesis of most myocardial infarction and ischemic stroke. Additionally, N-methyl-d-aspartate (NMDA) receptor plays a crucial role in myocardial infarction and ischemic strokes. The aim of our study was to investigate the underlying mechanisms of memantine (MEM), the blocker of NMDA receptors, in the development of atherosclerosis. In our study, human umbilical vascular endothelial cells (HUVECs) were stimulated with low-density lipoprotein (ox-LDL) to establish an atherosclerotic cell model. Cell Counting Kit-8 (CCK-8) assay and TUNEL staining were performed to detect the cell activity and apoptosis of HUVECs, respectively. The levels of inflammatory cytokines and malondialdehyde and the activities of lactate dehydrogenase (LDH), superoxide dismutase (SOD), and caspase-1 were quantified with commercial assay kits. Finally, qRT-PCR assay and western blot analysis were carried out to determine the mRNA and protein expressions of inflammation-related genes in HUVECs. The results of the present study suggested that ox-LDL stimulation induced decreased viability of HUVECs, excessive inflammation, and oxidative stress, while these effects were counteracted by MEM treatment. Interestingly, MEM triggered the activation of BDNF/TrkB signaling pathway in HUVECs, and K252a, the inhibitor of the BDNF/TrkB pathway, abolished the suppressive effect of MEM on ox-LDL-induced inflammation, oxidative stress, and apoptosis in HUVECs. Overall, MEM attenuated ox-LDL-induced inflammation, oxidative stress, and apoptosis via activation of BDNF/TrkB signaling pathway in HUVECs, indicating that MEM may be defined as a novel and effective agent for atherosclerosis treatment.

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Abbreviations

BDNF:

brain-derived neurotrophic factor

HUVECs:

human umbilical vascular endothelial cells

LDH:

lactate dehydrogenase

MEM:

memantine

NMDA:

N-methyl-d-aspartate

ox-LDL:

low-density lipoprotein

SOD:

superoxide dismutase

TrkB:

tropomyosin-related kinase receptor type B

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Funding

This work was supported by Key Disciplines Group Construction Project of Pudong Health Bureau of Shanghai, China (Grant No. PWZxq2017-05), and the Top-level Clinical Discipline Project of Shanghai Pudong, China (Grant No. PWYgf2018-02).

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Author notes

  1. Ying Hao and Rui Xiong contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, Shanghai East Hospital, Tongji University, 1800 Yuntai Rd, Shanghai, 200126, People’s Republic of China

    Ying Hao

  2. Department of Cornea, Affiliated Eye Hospital of Nanchang University, 463 Bayi Avenue, Nanchang City, 330006, Jiangxi Province, People’s Republic of China

    Rui Xiong

  3. Department of Cardiology, DeltaHealth Hospital, Shanghai, 201702, People’s Republic of China

    Xue Gong

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  1. Ying Hao
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  2. Rui Xiong
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Correspondence to Ying Hao or Rui Xiong.

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Hao, Y., Xiong, R. & Gong, X. Memantine, NMDA Receptor Antagonist, Attenuates ox-LDL-Induced Inflammation and Oxidative Stress via Activation of BDNF/TrkB Signaling Pathway in HUVECs. Inflammation 44, 659–670 (2021). https://doi.org/10.1007/s10753-020-01365-z

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