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细胞粘附分子L1的小分子激动剂在体内模拟L1功能。

Small Molecule Agonists of Cell Adhesion Molecule L1 Mimic L1 Functions In Vivo.

作者信息

Kataria Hardeep, Lutz David, Chaudhary Harshita, Schachner Melitta, Loers Gabriele

机构信息

Institut für Biosynthese Neuraler Strukturen, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum-Hamburg Eppendorf, Falkenried 94, 20251, Hamburg, Germany.

Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, 604 Allison Road, Piscataway, NJ, 08854, USA.

出版信息

Mol Neurobiol. 2016 Sep;53(7):4461-83. doi: 10.1007/s12035-015-9352-6. Epub 2015 Aug 8.

Abstract

Lack of permissive mechanisms and abundance of inhibitory molecules in the lesioned central nervous system of adult mammals contribute to the failure of functional recovery after injury, leading to severe disabilities in motor functions and pain. Peripheral nerve injury impairs motor, sensory, and autonomic functions, particularly in cases where nerve gaps are large and chronic nerve injury ensues. Previous studies have indicated that the neural cell adhesion molecule L1 constitutes a viable target to promote regeneration after acute injury. We screened libraries of known drugs for small molecule agonists of L1 and evaluated the effect of hit compounds in cell-based assays in vitro and in mice after femoral nerve and spinal cord injuries in vivo. We identified eight small molecule L1 agonists and showed in cell-based assays that they stimulate neuronal survival, neuronal migration, and neurite outgrowth and enhance Schwann cell proliferation and migration and myelination of neurons in an L1-dependent manner. In a femoral nerve injury mouse model, enhanced functional regeneration and remyelination after application of the L1 agonists were observed. In a spinal cord injury mouse model, L1 agonists improved recovery of motor functions, being paralleled by enhanced remyelination, neuronal survival, and monoaminergic innervation, reduced astrogliosis, and activation of microglia. Together, these findings suggest that application of small organic compounds that bind to L1 and stimulate the beneficial homophilic L1 functions may prove to be a valuable addition to treatments of nervous system injuries.

摘要

成年哺乳动物受损的中枢神经系统中缺乏允许性机制且存在大量抑制性分子,这导致损伤后功能恢复失败,进而导致运动功能严重残疾和疼痛。周围神经损伤会损害运动、感觉和自主神经功能,尤其是在神经间隙较大且发生慢性神经损伤的情况下。先前的研究表明,神经细胞黏附分子L1是促进急性损伤后再生的一个可行靶点。我们筛选了已知药物库以寻找L1的小分子激动剂,并在体外细胞实验以及体内股神经和脊髓损伤后的小鼠实验中评估了命中化合物的效果。我们鉴定出了8种小分子L1激动剂,并在细胞实验中表明它们能以L1依赖的方式刺激神经元存活、神经元迁移和神经突生长,增强雪旺细胞增殖、迁移以及神经元的髓鞘形成。在股神经损伤小鼠模型中,应用L1激动剂后观察到功能再生和髓鞘再生增强。在脊髓损伤小鼠模型中,L1激动剂改善了运动功能恢复,同时伴有髓鞘再生增强、神经元存活和单胺能神经支配增加、星形胶质细胞增生减少以及小胶质细胞激活。总之,这些发现表明,应用与L1结合并刺激有益的同源性L1功能的小有机化合物可能会成为神经系统损伤治疗的一项有价值的补充。

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