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Arctiin Mitigates Neuronal Injury by Modulating the P2X7R/NLPR3 Inflammasome Signaling Pathway

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Abstract

Depression, recognized globally as a primary cause of disability, has its pathogenesis closely related to neuroinflammation and neuronal damage. Arctiin (ARC), the major bioactive component of Fructus arctii, has various pharmacological activities, such as anti-inflammatory and neuroprotective effects. Building on previous findings that highlighted ARC's capability to mitigate depression by dampening microglial hyperactivation and thereby reducing neuroinflammatory responses and cortical neuronal damage in mice, the current study delves deeper into ARC's therapeutic potential by examining its impact on hippocampal neuronal damage in depression. Utilizing both chronic unpredictable mild stress (CUMS)-induced depression model in mice and corticosterone (CORT)-stimulated PC12 cell model of neuronal damage, the techniques including Nissl staining, immunohistochemistry, western blotting, ELISA, lactate dehydrogenase assays, colony formation assays, immunofluorescence staining and molecular docking were employed to unravel the mechanisms behind ARC's neuroprotective effects. The findings revealed that ARC not only mitigates hippocampal neuropathological damage and reduces serum CORT levels in CUMS-exposed mice but also enhances cell activity while reducing lactate dehydrogenase release in CORT-stimulated PC12 cells. ARC attenuated neuroinflammatory responses and neuronal apoptosis by inhibiting the overactivation of the P2X7 receptor (P2X7R)/NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling pathway, similar to the effect of A438079 (P2X7R antagonist). Interestingly, pretreatment with A438079 blocked the neuroprotective effect of ARC. Computer modeling predicted that both ARC and A438079 have strong binding with P2X7R and they have the same binding site. These results suggested that ARC may exert a neuroprotective role by binding to P2X7R, thereby inhibiting the P2X7R/NLRP3 inflammasome signaling pathway.

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Data Availability

No datasets were generated or analysed during the current study.

Abbreviations

ARC:

Arctiin

ASC:

Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain

CORT:

Corticosterone

CUMS:

Chronic unpredictable mild stress

DAPI:

4ʹ,6-Diamidino-2-phenylindole

DMSO:

Dimethyl sulfoxide

ELISA:

Enzyme-linked immunosorbent assay

IL-1β:

Interleukin-1β

LDH:

Lactate dehydrogenase

NLRP3:

NOD-like receptor family pyrin domain containing 3

PBS:

Phosphate-buffered saline

P2X7R:

P2X7 receptor

TLR4:

Toll-like receptor 4

TNF-α:

Tumor necrosis factor-alpha

TNFR1:

Tumor necrosis factor receptor 1

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Funding

This work was partially supported by the National Natural Science Foundation of China (81960375), the Jilin Provincial Science and Technology Department (YDZJ202201ZYTS294), Yanbian University Doctoral Research Fund Project (ydbq202218) and the Application Foundation Project of Yanbian University (ydkj202225).

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Author notes

  1. Guang-Nan Jin, Yu Wang and Yi-Ming Liu contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China

    Guang-Nan Jin, Yu Wang, Yu-Nan Lu, Jing-Mei Lu, Jing-He Wang, Jing-Wen Ma, Yan-Zhu Quan, Hong-Yan Gao, Xiang Xu & Lian-Xun Piao

  2. Department of Neurology, Yanbian University Hospital, Yanbian University, Yanji, 133000, Jilin Province, China

    Yi-Ming Liu & Yue-Xian Cui

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  1. Guang-Nan Jin
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  2. Yu Wang
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Contributions

GNJ contributed to investigation, data curation and writing—original draft. YW and YML contributed to investigation, data curation and writing. YNL, JML, JHW, JWM, YZQ and HYG contributed to investigation and data curation. YXC contributed to resources support. XX contributed to investigation, histopathology & formal analysis and writing—review & editing. LXP contributed to conceptualization, supervision, validation and writing—review & editing. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yue-Xian Cui, Xiang Xu or Lian-Xun Piao.

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Ethics Approval and Consent to Participate

All animal experiments were carried out according to the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals (National Institutes of Health Publication No. 80–23, revised 1996) and approved by the Institutional Animal Care Committee of Yanbian University Medical School (resolution number: 201501022). All efforts were made to minimize suffering and the number of animals used during the studies.

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The authors declare no competing interests.

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Jin, GN., Wang, Y., Liu, YM. et al. Arctiin Mitigates Neuronal Injury by Modulating the P2X7R/NLPR3 Inflammasome Signaling Pathway. Inflammation (2024). https://doi.org/10.1007/s10753-024-02117-z

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