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Caspofungin Suppresses Brain Cell Necroptosis in Ischemic Stroke Rats via Up-Regulation of Pellino3

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Abstract

Purpose

Pellino3, an ubiquitin E3 ligase, prevents the formation of the death-induced signaling complex in response to TNF-α by targeting receptor-interacting protein kinase 1 (RIPK1), and bioinformatics analysis predicted an interaction between Pellino3 and caspofungin, a common antifungal drug used in clinics. This study aimed to explore the effect of caspofungin on brain injury in ischemic stroke and the underlying mechanisms.

Methods

Ischemic stroke injury was induced in Sprague Dawley rats by occlusion of the middle cerebral artery (MCA) for 2 h, followed by 24 h reperfusion. PC12 cells were deprived of both oxygen and glucose for 8 h and then were cultured for 24 h with oxygen and glucose to mimic an ischemic stroke in vitro.

Results

Animal experiments showed brain injury (increase in neurological deficit score and infarct volume) concomitant with a downregulation of Pellino3, a decreased ubiquitination of RIPK1, and an up-regulation of necroptosis-associated proteins [RIPK1, RIPK3, mixed lineage kinase domain-like protein (MLKL), p-RIPK1, p-RIPK3, and p-MLKL]. Administration of caspofungin (6 mg/kg, i.m.) at 1 h and 6 h after ischemia significantly improved neurological function, reduced infarct volume, up-regulated Pellino3 levels, increased RIPK1 ubiquitination, and down-regulated protein levels of RIPK1, p-RIPK1, p-RIPK3, and p-MLKL. PC12 cells deprived of oxygen/glucose developed signs of cellular injury (LDH release and necroptosis) concomitant with downregulation of Pellino3, decreased ubiquitination of RIPK1, and elevated necroptosis-associated proteins. These changes were reversed by overexpression of Pellino3.

Conclusion

We conclude that Pellino3 has an important role in counteracting necroptosis via ubiquitination of RIPK1 and caspofungin can suppress the brain cell necroptosis in ischemic stroke through upregulation of Pellino3.

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Data Availability

Data are available upon request.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 82073849 to Xiu-Ju Luo, China, No. 81872873 to Jun Peng, China), Natural Science Foundation of Hunan Province, China (No. 2020JJ4770 to Jun Peng, China; No. 2020JJ4835 to Zhong-Yang Hu, China), Changsha Municipal Natural Science Foundation (No. kq2014145 to Xiu-Ju Luo, China), and Fundamental Research Funds for the Central Universities of Central South University (No. 2021zzts0329 to Yi-Yue Zhang, China; No. 1053320184093 to Jing Tian, China).

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Author notes

  1. Yi-Yue Zhang and Jing Tian contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China

    Yi-Yue Zhang, Jing Tian, Zi-Mei Peng, Bin Liu, Ya-Wei Peng, Xiao-Jie Zhang & Jun Peng

  2. Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China

    Xiao-Jie Zhang & Jun Peng

  3. Department of Neurology, The Third Xiangya Hospital of Central South University, Changsha, 410013, China

    Zhong-Yang Hu

  4. Department of Laboratory Medicine, The Third Xiangya Hospital of Central South University, Changsha, 410013, China

    Xiu-Ju Luo

Authors
  1. Yi-Yue Zhang
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  2. Jing Tian
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Contributions

Jun Peng, Xiu-Ju Luo, and Xiao-Jie Zhang conceived and designed the study. Yi-Yue Zhang, Jing Tian, Zi-Mei Peng, and Ya-Wei Peng conducted the experiments. Yi-Yue Zhang, Bin Liu, and Zhong-Yang Hu analyzed the data. Yi-Yue Zhang, Xiu-Ju Luo, and Jun Peng wrote the manuscript. All authors read and approved the manuscript.

Corresponding authors

Correspondence to Xiu-Ju Luo or Jun Peng.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants.

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Zhang, YY., Tian, J., Peng, ZM. et al. Caspofungin Suppresses Brain Cell Necroptosis in Ischemic Stroke Rats via Up-Regulation of Pellino3. Cardiovasc Drugs Ther 37, 9–23 (2023). https://doi.org/10.1007/s10557-021-07231-w

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  • DOI: https://doi.org/10.1007/s10557-021-07231-w

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