Chemical modulation of Akt signaling enhances spinal cord regeneration in zebrafish

Yang-Jin Shen; Hao-Yuan Chen; Chia-Wei Chang; Yin-Cheng Huang; Yi-Chuan Cheng

doi:10.1016/j.brainres.2024.149248

Chemical modulation of Akt signaling enhances spinal cord regeneration in zebrafish

Brain Res. 2024 Sep 21:1846:149248. doi: 10.1016/j.brainres.2024.149248. Online ahead of print.

Authors

Yang-Jin Shen¹, Hao-Yuan Chen², Chia-Wei Chang², Yin-Cheng Huang³, Yi-Chuan Cheng⁴

Affiliations

¹ Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; School of Medicine, Chang Gung University, Taoyuan, Taiwan.
² Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
³ Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁴ Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan. Electronic address: yccheng@mail.cgu.edu.tw.

PMID: 39313168
DOI: 10.1016/j.brainres.2024.149248

Abstract

Central nervous system lesions often cause permanent motility defects in mammals since the injured neurons cannot regenerate. In contrast, lower vertebrates like zebrafish can regenerate lost neurons and restore motor function. This study investigates the efficacy of SC79, a pan-Akt activator, and A674563, a selective Akt1 inhibitor, as potential therapeutic agents for promoting spinal cord recovery post-injury. Spinal cord injury was induced in zebrafish larvae, and the effects of SC79 and A674563 on neuronal and glial regeneration were examined. SC79 promoted neuronal regeneration without affecting glial bridging, while A674563 induced glial bridging but reduced neuronal regeneration. The combination of SC79 and A674563 induced both glial bridging and neuronal regeneration. Optomotor response tests revealed improved motor function recovery with the combined treatment compared to individual treatments. Additionally, these chemical treatments altered the expression of 12 Akt downstream transcriptional target genes, affirming that the combination treatment preferentially regulates spinal cord regeneration through its action on Akt signaling. These findings highlight the complex interplay of Akt signaling pathways in spinal cord regeneration and suggest potential therapeutic strategies for enhancing functional recovery in spinal cord injury patients.

Keywords: Akt signaling; Spinal cord regeneration; Zebrafish.