Inhibition of autophagy-dependent pyroptosis attenuates cerebral ischaemia/reperfusion injury.

Abstract

Autophagy is closely associated with cerebral ischaemia/reperfusion injury, but the underlying mechanisms are unknown. We investigated whether Spautin-1 ameliorates cerebral ischaemia/reperfusion injury by inhibiting autophagy and whether its derived pyroptosis is involved in this process. We explored the mechanism of Spautin-1 in cerebral ischaemia/reperfusion. To answer these questions, healthy male Sprague-Dawley rats were exposed to middle cerebral artery occlusion for 60 minutes followed by reperfusion for 24 hours. We found that cerebral ischaemia/reperfusion increased the expression levels of autophagy and pyroptosis-related proteins. Treatment with Spautin-1 reduced the infarct size and water content and restored some neurological functions. In vitro experiments were performed using oxygen-glucose deprivation/reoxygenation to model PC12 cells. The results showed that PC12 cells showed a significant decrease in cell viability and a significant increase in ROS and autophagy levels. Spautin-1 treatment reduced autophagy and ROS accumulation and attenuated NLRP3 inflammasome-dependent pyroptosis. However, these beneficial effects were greatly blocked by USP13 overexpression, which significantly counteracted the inhibition of autophagy and NLRP3 inflammasome-dependent ferroptosis by Spautin-1. Together, these results suggest that Spautin-1 may ameliorate cerebral ischaemia-reperfusion injury via the autophagy/pyroptosis pathway. Thus, inhibition of autophagy may be considered as a promising therapeutic approach for cerebral ischaemia-reperfusion injury.

• Authors: Hui Liu, Zongbo Zhao, Tao Wu, Qiu Zhang, Fenying Lu, Jie Gu, Tingwang Jiang, Jianzhong Xue
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 25 Issue 11 Pg. 5060-5069 (06 2021) ISSN: 1582-4934 [Electronic] England
• PMID: 33938129 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Neuroprotective Agents

Topics

• Animals
• Autophagy
• Brain Ischemia (etiology, metabolism, pathology, prevention & control)
• Disease Models, Animal
• Infarction, Middle Cerebral Artery (complications)
• Male
• Neuroprotective Agents (pharmacology)
• PC12 Cells
• Pyroptosis
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (etiology, metabolism, pathology, prevention & control)