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Inhibition of Noncanonical Ca2+ Oscillation/Calcineurin/GSK-3β Pathway Contributes to Anti-Inflammatory Effect of Sigma-1 Receptor Activation

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Abstract

Further understanding the mechanism for microglia activation is necessary for developing novel anti-inflammatory strategies. Our previous study found that the activation of sigma-1 receptor can effectively inhibit the neuroinflammation, independent of the canonical mechanisms, such as NF-κB, JNK and ERK inflammatory pathways. Thus, it is reasonable that an un-identified, non-canonical pathway contributes to the activation of microglia. In the present study, we found that a sigma-1 receptor agonist of 2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate (PRE-084) suppressed lipopolysaccharide (LPS) elevated nitric oxide (NO) content in BV-2 microglia culture supernatant and LPS-raised mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS) in BV-2 microglia. Moreover, PRE-084 alleviated LPS-increased Ser 9 de-phosphorylation of glycogen synthase kinase-3 beta (GSK-3β), LPS-elevated catalytic activity of calcineurin, and LPS-raised percent and frequency of Ca2+ oscillatory BV-2 cells. We further found that the inhibitory effect of PRE-084 was reversed by a calcineurin activator of chlorogenic acid and a GSK-3β activator of pyrvinium. Moreover, an IP3 receptor inhibitor of 2-aminoethoxydiphenyl borate mimicked the anti-inflammatory activity of PRE-084. Thus, we identified a noncanonical pro-neuroinflammary pathway of Ca2+ oscillation/Calcineurin/GSK-3β and the inhibition of this pathway is necessary for the anti-inflammatory activity of sigma-1 receptor activation.

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Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

2-APB:

2-Aminoethoxydiphenyl borate

BD1047:

N′-[2-(3,4-dichlorophenyl)ethyl]-N,N, N′-trimethylethane-1,2-diamine

CGA:

Chlorogenic acid

ERK:

Extracellular-signal-regulated kinase

JNK:

C-Jun N terminal kinase

IKK:

IκB kinase

iNOS:

Inducible nitric oxide synthase

IκBα:

Inhibitor of nuclear factor-κB, α

IL-1β:

Interleukin-1β

IL-10:

Interleukin-10

IP3 :

Inositol triphosphate

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase

MTT:

3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyl tetrazoliumbromide

Nrf2:

Nuclear factor erythroid-2 related factor 2

NO:

Nitric oxide

PRE-084:

2-Morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate

ROS:

Reactive oxygen species

S1R:

Sigma-1 receptor

SKF83959:

3-Methyl-6-chloro-7,8-hydroxy-1-(3-methylphenyl)-2, 3, 4, 5-tetrahydro-1H-3-benzazepine

SOCE:

Store-operated Ca2+ entry TGF-β, transforming growth factor-β

TNF-α:

Tumor necrosis factor-α

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Funding

This project was supported by grants from the National Natural Science Foundation of China (Grant No. 81872847, 82173803). Supports provided from the Priority Academic Program Development of Jiangsu Higher Education Institutes (PAPD) and Jiangsu Overseas Visiting Scholar Program for University Prominent Young and Middle-Aged Teacher and President are also appreciated.

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Author notes

  1. Tianyu Gao and Ce Gao have contributed equally to this work.

Authors and Affiliations

  1. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221000, Jiangsu Province, China

    Tianyu Gao, Ce Gao, Yun Wang, Xiaoxia Jia, Qian Lu & Lin Guo

  2. Department of Pharmacy, The Affiliated Hospital of Xuzhou Medical University, 99 West Huai-hai Road, Xuzhou, 221004, Jiangsu Province, China

    Tianyu Gao, Ce Gao, Zhidong Liu & Lin Guo

  3. Agro-Products Processing Research Institute, Yunnan Academy of Agricultural Sciences, 2238 Beijing Road, Kunming, 650000, Yunnan Province, China

    Hao Tian

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  1. Tianyu Gao
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Contributions

Investigation, writing—original draft: [TG]; investigation: [CG]; investigation: [ZL]; conceptualization, funding acquisition: [YW]; investigation: [XJ]; investigation: [HT]; supervision, writing—review & editing: [QL]; conceptualization, funding acquisition, supervision, writing—review & editing: [LG].

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Correspondence to Qian Lu or Lin Guo.

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Gao, T., Gao, C., Liu, Z. et al. Inhibition of Noncanonical Ca2+ Oscillation/Calcineurin/GSK-3β Pathway Contributes to Anti-Inflammatory Effect of Sigma-1 Receptor Activation. Neurochem Res 47, 264–278 (2022). https://doi.org/10.1007/s11064-021-03439-2

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