Laboratories for Neuroscience Research in Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States; F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States; Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States.
Laboratories for Neuroscience Research in Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States; F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States; Department of Neurosurgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States.
Exp Neurol. 2018 Feb;300:22-29. doi: 10.1016/j.expneurol.2017.10.025. Epub 2017 Oct 27.
The inability of axons to regenerate over long-distances in the central nervous system (CNS) limits the recovery of sensory, motor, and cognitive functions after various CNS injuries and diseases. Although pre-clinical studies have identified a number of manipulations that stimulate some degree of axon growth after CNS damage, the extent of recovery remains quite limited, emphasizing the need for improved therapies. Here, we used traumatic injury to the mouse optic nerve as a model system to test the effects of combining several treatments that have recently been found to promote axon regeneration without the risks associated with manipulating known tumor suppressors or oncogenes. The treatments tested here include TPEN, a chelator of mobile (free) zinc (Zn); shRNA against the axon growth-suppressing transcription factor Klf9; and the atypical growth factor oncomodulin combined with a cAMP analog. Whereas some combinatorial treatments produced only marginally stronger effects than the individual treatments alone, co-treatment with TPEN and Klf9 knockdown had a substantially stronger effect on axon regeneration than either one alone. This combination also promoted a high level of cell survival at longer time points. Thus, Zn chelation in combination with Klf9 suppression holds therapeutic potential for promoting axon regeneration after optic nerve injury, and may also be effective for treating other CNS injuries and diseases.
轴突在中枢神经系统 (CNS) 中无法远距离再生，限制了各种 CNS 损伤和疾病后感觉、运动和认知功能的恢复。尽管临床前研究已经确定了许多可以刺激 CNS 损伤后一定程度轴突生长的操作，但恢复的程度仍然相当有限，这强调了需要改进治疗方法。在这里，我们使用小鼠视神经创伤作为模型系统，测试了几种治疗方法联合应用的效果，这些治疗方法最近被发现可以促进轴突再生，而不会带来操纵已知肿瘤抑制因子或致癌基因的风险。这里测试的治疗方法包括 TPEN，一种移动（游离）锌 (Zn) 的螯合剂；针对轴突生长抑制转录因子 Klf9 的 shRNA；以及与 cAMP 类似物结合的非典型生长因子 oncomodulin。虽然一些组合治疗的效果仅比单独治疗略有增强，但 TPEN 和 Klf9 敲低的联合治疗对轴突再生的效果比单独一种治疗要强得多。这种组合还在更长的时间点促进了高水平的细胞存活。因此，Zn 螯合与 Klf9 抑制联合具有在视神经损伤后促进轴突再生的治疗潜力，并且可能对治疗其他 CNS 损伤和疾病也有效。
