Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; School of Medicine, Chang Gung University, Taoyuan, Taiwan.
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Brain Res. 2025 Jan 1;1846:149248. doi: 10.1016/j.brainres.2024.149248. Epub 2024 Sep 21.
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.
中枢神经系统损伤常导致哺乳动物出现永久性运动缺陷，因为受损神经元无法再生。相比之下，斑马鱼等较低等的脊椎动物可以再生丢失的神经元并恢复运动功能。本研究探讨了 pan-Akt 激活剂 SC79 和选择性 Akt1 抑制剂 A674563 作为促进脊髓损伤后恢复的潜在治疗药物的功效。在斑马鱼幼虫中诱导脊髓损伤，并研究了 SC79 和 A674563 对神经元和神经胶质再生的影响。SC79 促进神经元再生而不影响神经胶质桥接，而 A674563 诱导神经胶质桥接但减少神经元再生。SC79 和 A674563 的组合诱导了神经胶质桥接和神经元再生。光反应测试显示，与单独治疗相比，联合治疗可改善运动功能的恢复。此外，这些化学处理改变了 12 个 Akt 下游转录靶基因的表达，证实联合治疗通过其对 Akt 信号通路的作用优先调节脊髓再生。这些发现强调了 Akt 信号通路在脊髓再生中的复杂相互作用，并为增强脊髓损伤患者的功能恢复提供了潜在的治疗策略。
