Horie Hidenori, Kadoya Toshihiko, Sango Kazunori, Hasegawa Mitsuhiro
Advanced Research Center for Biological Science, Waseda University, Waseda University Higashifushimi Campus, Nishitokyo City, Tokyo, Japan.
Curr Drug Targets. 2005 Jun;6(4):385-94. doi: 10.2174/1389450054021954.
Although many factors have been implicated in the regenerative response of peripheral axons to nerve injury, the signals that prompt neurons to extend processes in peripheral nerves after axotomy are not well-understood. As shown in the first chapter, oxidized recombinant human galectin-1 (rhGAL-1/Ox), which lacks lectin activity, promotes initial axonal growth in an in vitro peripheral nerve regeneration model at low concentrations (pg/ml). At a similarly low concentration, rhGAL-1/Ox has also been shown to be effective in enhancing axonal regeneration using in vivo experiments. Moreover, the application of functional anti-rhGAL-1 antibody strongly inhibited axonal regeneration in vivo as well as in vitro. Since galectin-1 (GAL-1) is expressed in the regenerating sciatic nerves as well as in both sensory and motoneurons, these results indicate that GAL-1, which is secreted into the extracellular space, is subsequently oxidized and then may regulate initial repair after axotomy. This possibility was confirmed by Western blot analysis, which revealed that both reduced and oxidized forms of GAL-1 are present in culture media of DRG neurons and immortalized adult mouse Schwann cells (IMS32). Externalized GAL-1/Ox has been found to stimulate macrophages to secrete an axonal regeneration-promoting factor. From these results, we propose that axonal regeneration occurs in axotomized peripheral nerves as a result of cytosolic reduced GAL-1 being released from Schwann cells and injured axons, which then becomes oxidized in the extracellular space. GAL-1/Ox in the extracellular space stimulates macrophages to secrete a factor that promotes axonal growth and Schwann cell migration, thus enhancing peripheral nerve regeneration and functional recovery. These results suggest that rhGAL-1/Ox may be a novel factor for functional restoration of injured peripheral nerves.
尽管许多因素与外周轴突对神经损伤的再生反应有关，但在轴突切断后促使神经元在外周神经中延伸突起的信号仍未得到充分理解。如第一章所示，缺乏凝集素活性的氧化重组人半乳糖凝集素-1（rhGAL-1/Ox）在低浓度（pg/ml）下可促进体外外周神经再生模型中的初始轴突生长。在同样低的浓度下，rhGAL-1/Ox在体内实验中也被证明对增强轴突再生有效。此外，功能性抗rhGAL-1抗体的应用在体内和体外均强烈抑制轴突再生。由于半乳糖凝集素-1（GAL-1）在再生的坐骨神经以及感觉神经元和运动神经元中均有表达，这些结果表明，分泌到细胞外空间的GAL-1随后被氧化，然后可能调节轴突切断后的初始修复。蛋白质印迹分析证实了这种可能性，该分析显示GAL-1的还原形式和氧化形式均存在于背根神经节神经元和永生化成年小鼠雪旺细胞（IMS32）的培养基中。已发现外化的GAL-1/Ox可刺激巨噬细胞分泌一种促进轴突再生的因子。基于这些结果，我们提出，轴突切断后的外周神经中发生轴突再生是由于雪旺细胞和受损轴突释放的胞质还原型GAL-1，其随后在细胞外空间被氧化。细胞外空间中的GAL-1/Ox刺激巨噬细胞分泌一种促进轴突生长和雪旺细胞迁移的因子，从而增强外周神经再生和功能恢复。这些结果表明，rhGAL-1/Ox可能是促进受损外周神经功能恢复的一种新因子。
