Department of Biomedical Sciences, College of Medicine, Korea University, Ansan, 15335, Republic of Korea.
Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, 08554, USA.
Sci Rep. 2021 Mar 15;11(1):5878. doi: 10.1038/s41598-021-85412-1.
Demyelination leads to a loss of neurons, which results in, among other consequences, a severe reduction in locomotor function, and underlies several diseases in humans including multiple sclerosis and polyneuropathies. Considerable clinical progress has been made in counteracting demyelination. However, there remains a need for novel methods that reduce demyelination while concomitantly achieving remyelination, thus complementing the currently available tools to ameliorate demyelinating diseases. In this study, we used an established zebrafish demyelination model to test selected compounds, following a screening in cell culture experiments and in a mouse model of spinal cord injury that was aimed at identifying beneficial functions of the neural cell adhesion molecule L1. In comparison to mammalian nervous system disease models, the zebrafish allows testing of potentially promotive compounds more easily than what is possible in mammals. We found that our selected compounds tacrine and duloxetine significantly improved remyelination in the peripheral and central nervous system of transgenic zebrafish following pharmacologically induced demyelination. Given that both molecules are known to positively affect functions other than those related to L1 and in other disease contexts, we propose that their combined beneficial function raises hope for the use of these compounds in clinical settings.
脱髓鞘导致神经元丧失，这导致运动功能严重受损，是包括多发性硬化症和多发性神经病在内的多种人类疾病的基础。在对抗脱髓鞘方面已经取得了相当大的临床进展。然而，仍然需要新的方法来减少脱髓鞘，同时实现髓鞘再生，从而补充目前可用的工具来改善脱髓鞘疾病。在这项研究中，我们使用了一种已建立的斑马鱼脱髓鞘模型来测试选定的化合物，这些化合物是在细胞培养实验和脊髓损伤的小鼠模型中筛选出来的，旨在确定神经细胞粘附分子 L1 的有益功能。与哺乳动物神经系统疾病模型相比，斑马鱼可以更容易地测试潜在的促进化合物，而这在哺乳动物中是不可能的。我们发现，我们选择的化合物他克林和度洛西汀在药物诱导的脱髓鞘后显著改善了转基因斑马鱼中枢和外周神经系统的髓鞘再生。鉴于这两种分子已知对与 L1 无关的其他功能以及其他疾病环境具有积极影响，我们提出，它们的联合有益作用为这些化合物在临床环境中的应用带来了希望。
