Caspofungin Suppresses Brain Cell Necroptosis in Ischemic Stroke Rats via Up-Regulation of Pellino3
- 08.09.2021
- Original Article
Erschienen in:
- Verfasst von
- Yi-Yue Zhang
- Jing Tian
- Zi-Mei Peng
- Bin Liu
- Ya-Wei Peng
- Xiao-Jie Zhang
- Zhong-Yang Hu
- Xiu-Ju Luo
- Jun Peng
- Erschienen in
- Cardiovascular Drugs and Therapy | Ausgabe 1/2023
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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- Titel
- Caspofungin Suppresses Brain Cell Necroptosis in Ischemic Stroke Rats via Up-Regulation of Pellino3
- Verfasst von
-
Yi-Yue Zhang
Jing Tian
Zi-Mei Peng
Bin Liu
Ya-Wei Peng
Xiao-Jie Zhang
Zhong-Yang Hu
Xiu-Ju Luo
Jun Peng
- Publikationsdatum
- 08.09.2021
- Verlag
- Springer US
- Erschienen in
-
Cardiovascular Drugs and Therapy / Ausgabe 1/2023
Print ISSN: 0920-3206
Elektronische ISSN: 1573-7241 - DOI
- https://doi.org/10.1007/s10557-021-07231-w
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