Int J Biol Sci 2021; 17(4):1138-1152. doi:10.7150/ijbs.57825 This issue

Research Paper

Betulinic acid inhibits pyroptosis in spinal cord injury by augmenting autophagy via the AMPK-mTOR-TFEB signaling pathway

Chenyu Wu1,2*, Huanwen Chen3*, Rong Zhuang4, Haojie Zhang1,2, Yongli Wang5, Xinli Hu1,2, Yu Xu1,2, Jiafeng Li1,2, Yao Li1,2, Xiangyang Wang1,2, Hui Xu1,2✉, Wenfei Ni1,2✉, Kailiang Zhou1,2✉

1. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China.
2. Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China.
3. University of Maryland School of Medicine, Baltimore, MD 21201, USA.
4. Department of Anesthesiology, Critical Care and Pain Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China.
5. Department of Orthopaedics, Huzhou Central Hospital, Huzhou 313000, China.
*These authors contributed equally to this work.

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Citation:
Wu C, Chen H, Zhuang R, Zhang H, Wang Y, Hu X, Xu Y, Li J, Li Y, Wang X, Xu H, Ni W, Zhou K. Betulinic acid inhibits pyroptosis in spinal cord injury by augmenting autophagy via the AMPK-mTOR-TFEB signaling pathway. Int J Biol Sci 2021; 17(4):1138-1152. doi:10.7150/ijbs.57825. Available from https://www.ijbs.com/v17p1138.htm

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Abstract

Graphic abstract

Spinal cord injury (SCI) results in a wide range of disabilities. Its complex pathophysiological process limits the effectiveness of many clinical treatments. Betulinic acid (BA) has been shown to be an effective treatment for some neurological diseases, but it has not been studied in SCI. In this study, we assessed the role of BA in SCI and investigated its underlying mechanism. We used a mouse model of SCI, and functional outcomes following injury were assessed. Western blotting, ELISA, and immunofluorescence techniques were employed to analyze levels of autophagy, mitophagy, pyroptosis, and AMPK-related signaling pathways were also examined. Our results showed that BA significantly improved functional recovery following SCI. Furthermore, autophagy, mitophagy, ROS level and pyroptosis were implicated in the mechanism of BA in the treatment of SCI. Specifically, our results suggest that BA restored autophagy flux following injury, which induced mitophagy to eliminate the accumulation of ROS and inhibits pyroptosis. Further mechanistic studies revealed that BA likely regulates autophagy and mitophagy via the AMPK-mTOR-TFEB signaling pathway. Those results showed that BA can significantly promote the recovery following SCI and that it may be a promising therapy for SCI.

Keywords: Betulinic acid, autophagy, mitophagy, pyroptosis, spinal cord injury