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N-acetylserotonin Derivative Exerts a Neuroprotective Effect by Inhibiting the NLRP3 Inflammasome and Activating the PI3K/Akt/Nrf2 Pathway in the Model of Hypoxic-Ischemic Brain Damage

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Abstract

Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the main causes of neonatal disability and death. As a derivative of N-acetylserotonin, N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide (HIOC) can easily cross the blood–brain barrier and have a long half-life in the brain. In this study, the hypothesis was verified that HIOC plays a neuroprotective role in the HIE model and its potential mechanism was evaluated. Firstly, an HIE rat model was established to deliver HIOC, revealing that it can reduce cerebral infarction volume, cerebral edema, and neuronal apoptosis. The results of immunofluorescence staining, Western blots and RT-PCR further showed that HIOC could inhibit the activation of the NLRP3 inflammasome and the expression of related proteins. Finally, the activation of the phosphatidylinositol-3-kinase (PI3K)/Akt/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by HIOC was verified in vitro and in vivo. It was discovered that HIOC could increase the nuclear translocation of Nrf2, and that this induction can be reversed by the PI3K/Akt pathway inhibitor LY294002. In general terms, the neuroprotective effect of HIOC was confirmed in the HIE model, which is related to the activation of the Pi3k/Akt/Nrf2 signal pathway and the inhibition of the NLRP3 inflammasome.

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Abbreviations

Akt:

Protein kinase B

DAPI:

4′,6-diamidino-2-phenylindole

HIE:

Hypoxic-ischemic encephalopathy

HIOC:

N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide

HO-1:

Heme oxygenase-1

Iba-1:

Ionized calcium binding adapter molecule 1

IL:

Interleukin

NAS:

N-acetylserotonin

Nrf2:

Nuclear factor erythroid 2-related factor 2

PI3K:

Phosphatidylinositol 3-kinase

TNF-α:

Tumor necrosis factor-α

TTC:

2, 3, 5-triphenyltetrazolium chloride

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

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Funding

This work was supported by grants from the Central Fund for Guiding Local Science and Technology Development (No. [2016]109) and Natural Science Foundation of Hubei Province (No. WJ2019M184).

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Authors and Affiliations

  1. Departments of Neonatology, Renmin Hospital of Wuhan University, Ziyang Road Wuchang District, No. 99 Jiefang Road, Wuhan, 430060, Hubei Province, China

    Xing Luo, Honglan Zeng,  Chengzhi Fang & Bing-Hong Zhang

  2. Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China

    Xing Luo

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  1. Xing Luo
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  2. Honglan Zeng
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Correspondence to Chengzhi Fang or Bing-Hong Zhang.

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All animal experiment programs are approved by the Animal Experimental Ethics Committee at Wuhan University and conducted in accordance with the guidance of the Animal Care and use Committee of Renmin Hospital at Wuhan University (Approval number: WDRM 20190315). Efforts were made to minimize the number of rats and their suffering.

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Luo, X., Zeng, H., Fang, . et al. N-acetylserotonin Derivative Exerts a Neuroprotective Effect by Inhibiting the NLRP3 Inflammasome and Activating the PI3K/Akt/Nrf2 Pathway in the Model of Hypoxic-Ischemic Brain Damage. Neurochem Res 46, 337–348 (2021). https://doi.org/10.1007/s11064-020-03169-x

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  • DOI: https://doi.org/10.1007/s11064-020-03169-x

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