Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (on line): 1-11.

   

Davunetide promotes structural and functional recovery of the injured spinal cord by promoting autophagy

Yituo Chen1, 2, 3, #, Rongjie Liu1, 2, 3, #, Wanta Cai1, 2, 3, Liting Jiang1, 2, 3, Kongbin Chen1, 2, 3, Jingwei Shi4 , Junsheng Lou5 , Letian Yu6 , Chenyu Wu1, 2, 3, Liangliang Yang4, 7, *, Kailiang Zhou1, 2, 3, *, Wenfei Ni1, 2, 3,*   

  1. 1 Department of Orthopedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; 2 Zhejiang Provincial Key Laboratory of Orthopedics, Wenzhou, Zhejiang Province, China; 3 The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; 4 Cixi Biomedical Research Institute, Wenzhou Medical University, Ningbo, Zhejiang Province, China; 5 Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; 6 Renji College of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; 7 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang Provine, China
  • Online:2025-01-01 Published:2025-03-06
  • Contact: Liangliang Yang, MD, PhD, liangliangyangLLL@126.com; Kailiang Zhou, MD, PhD, zhoukailiang@wmu.edu.cn; Wenfei Ni, MD, PhD, niwenfei@126.com.
  • Supported by:
    This study was supported by the Natural Science Foundation of Zhejiang Province, No. LY21H060009 (to WN); National Natural Science Foundation of China, Nos. 82072192 and 82372540 (to KZ); Medical and Health Technology Plan Project of Zhejiang Province, No. 2024KY155 (to KZ); Natural Science Foundation of Ningbo, No. 2023J256 (to KZ); Science and Technology Bureau Foundation of Wenzhou, No. Y20220211 (to CW).

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Abstract: After spinal cord injury, programmed cell death is common. In this context, autophagy plays a crucial role in clearing cellular debris, while necroptosis exacerbates neuroinflammation and further damages neural structures. The neuroprotective drug davunetide has shown substantial therapeutic effects on brain diseases, but its role in treating spinal cord injury remains unclear. Therefore, the aim of this study was to investigate the effects of davunetide on cell death after spinal cord injury. To do this, we established a mouse model of spinal cord contusion and administered davunetide intranasally daily at a dose of 0.5 µg/5 µL. Mouse locomotor function was assessed using footprint analysis and Basso Mouse Scale scoring, while the extent of spinal cord injury was evaluated using Masson’s trichrome staining. The expression levels of proteins related to locomotor function and spinal cord injury were analyzed by Western blotting and immunofluorescence staining, and protein–protein interactions were evaluated using immunoprecipitation techniques. Our results demonstrated that davunetide not only reduced the size of the injury area but also promoted the recovery of locomotor function after spinal cord injury. Specifically, davunetide exerted its effects by enhancing autophagy and inhibiting necroptosis. Inhibition of autophagy reversed the protective effects of davunetide on necroptosis. Further investigation revealed that davunetide acted through the SIRT1-FOXO1-TFEB signaling pathway, which is key to its therapeutic effects. These findings suggest the potential of davunetide in the treatment of spinal cord injury and provide valuable insights into the underlying mechanisms. This study offers strong scientific evidence to support the development of new therapeutic strategies for spinal cord injury.

Key words: autophagy, davunetide, locomotor function recovery, NAP, necroptosis, neuron, Sirtuin1, spinal cord injury, transcription factor EB