Trimebutine, a small molecule mimetic agonist of adhesion molecule L1, contributes to functional recovery after spinal cord injury in mice.
Trimebutine, a small molecule mimetic agonist of adhesion molecule L1, contributes to functional recovery after spinal cord injury in mice.
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DOI：
10.1242/dmm.029801
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发表时间：
2017-09-01
影响因子：
4.3
通讯作者：
Schachner M
中科院分区：
文献类型：
--
作者：
Xu J;Hu C;Jiang Q;Pan H;Shen H;Schachner M
治疗哺乳动物的脊髓损伤（SCI）是一项艰巨的任务，因为在病变处及其周围缺乏允许机制和强烈的抑制反应。神经细胞粘附分子L1 CAM（L1）已被证明有利于轴突再生，并增强神经元的存活和突触可塑性，但全长L1或其胞外结构域的交付可能会遇到困难，在人类的治疗翻译。因此，我们已经确定了几个小的有机化合物，结合到L1和刺激神经元的生存，神经元迁移和轴突生长的L1依赖的方式。在这里，我们评估的功能，两个L1模拟，曲美布汀和honokaline，脊髓损伤后再生年轻成年小鼠。使用Basso小鼠量表（BMS）评分，我们发现曲美布汀治疗的小鼠的地面运动恢复得比和厚朴酚治疗或接受载体的小鼠更好。曲美布汀组在SCI后6周观察到后肢运动功能增强。 脊髓的喙部和尾部的病变部位的免疫组织化学显示减少的面积和强度的胶质细胞酸性蛋白免疫反应性在曲美布汀和honoklastine组，而增加的轴突再生只观察到在曲美布汀治疗组。曲美布汀和honokaline激活了脊髓损伤部位的L1和L1模拟介导的细胞内信号级联，曲美布汀比honokaline更有效。这些观察结果表明，曲美布汀，在本实验条件下，在较小程度上，honokaline有一个潜在的治疗哺乳动物脊髓损伤的再生。摘要：小分子L1CAM模拟物，显示L1功能，促进神经突生长和神经元存活在体外，现在显示在体内，与相关的信号转导，以促进损伤后的恢复。
Curing spinal cord injury (SCI) in mammals is a daunting task because of the lack of permissive mechanisms and strong inhibitory responses at and around the lesion. The neural cell adhesion molecule L1CAM (L1) has been shown to favor axonal regrowth and enhance neuronal survival and synaptic plasticity but delivery of full-length L1 or its extracellular domain could encounter difficulties in translation to therapy in humans. We have, therefore, identified several small organic compounds that bind to L1 and stimulate neuronal survival, neuronal migration and neurite outgrowth in an L1-dependent manner. Here, we assessed the functions of two L1 mimetics, trimebutine and honokiol, in regeneration following SCI in young adult mice. Using the Basso Mouse Scale (BMS) score, we found that ground locomotion in trimebutine-treated mice recovered better than honokiol-treated or vehicle-receiving mice. Enhanced hindlimb locomotor functions in the trimebutine group were observed at 6 weeks after SCI. Immunohistology of the spinal cords rostral and caudal to the lesion site showed reduced areas and intensities of glial fibrillary acidic protein immunoreactivity in both trimebutine and honokiol groups, whereas increased regrowth of axons was observed only in the trimebutine-treated group. Both L1- and L1 mimetic-mediated intracellular signaling cascades in the spinal cord lesion sites were activated by trimebutine and honokiol, with trimebutine being more effective than honokiol. These observations suggest that trimebutine and, to a lesser extent under the present experimental conditions, honokiol have a potential for therapy in regeneration of mammalian spinal cord injuries. Summary: Small molecule L1CAM mimetics, showing L1 functions by promoting neurite outgrowth and neuronal survival in vitro, are now shown in vivo, with correlated signal transduction, to promote recovery after injury.
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DOI：
10.1083/jcb.137.3.703
发表时间：
1997-05-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Garver TD;Ren Q;Tuvia S;Bennett V
通讯作者：
Bennett V
影响因子：
4.3
作者：
Kanno, Haruo;Ozawa, Hiroshi;Itoi, Eiji
通讯作者：
Itoi, Eiji
DOI：
10.1080/147342202753203087
发表时间：
2002-01-01
期刊：
Cerebellum (London, England)
影响因子：
--
作者：
Contestabile, Antonio
通讯作者：
Contestabile, Antonio
DOI：
10.1007/bf01183975
发表时间：
1993-01-01
期刊：
JOURNAL OF NEUROCYTOLOGY
影响因子：
--
作者：
CURTIS, R;GREEN, D;WILKIN, GP
通讯作者：
WILKIN, GP
影响因子：
4.7
作者：
Loers, Gabriele;Saini, Vedangana;Kaur, Gurcharan
通讯作者：
Kaur, Gurcharan