Cellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, CT, USA.
Exp Neurol. 2012 Sep;237(1):55-69. doi: 10.1016/j.expneurol.2012.06.009. Epub 2012 Jun 21.
Several pharmacological approaches to promote neural repair and recovery after CNS injury have been identified. Blockade of either astrocyte-derived chondroitin sulfate proteoglycans (CSPGs) or oligodendrocyte-derived NogoReceptor (NgR1) ligands reduces extrinsic inhibition of axonal growth, though combined blockade of these distinct pathways has not been tested. The intrinsic growth potential of adult mammalian neurons can be promoted by several pathways, including pre-conditioning injury for dorsal root ganglion (DRG) neurons and macrophage activation for retinal ganglion cells (RGCs). Singly, pharmacological interventions have restricted efficacy without foreign cells, mechanical scaffolds or viral gene therapy. Here, we examined combinations of pharmacological approaches and assessed the degree of axonal regeneration. After mouse optic nerve crush injury, NgR1-/- neurons regenerate RGC axons as extensively as do zymosan-injected, macrophage-activated WT mice. Synergistic enhancement of regeneration is achieved by combining these interventions in zymosan-injected NgR1-/- mice. In rats with a spinal dorsal column crush injury, a preconditioning peripheral sciatic nerve axotomy, or NgR1(310)ecto-Fc decoy protein treatment or ChondroitinaseABC (ChABC) treatment independently support similar degrees of regeneration by ascending primary afferent fibers into the vicinity of the injury site. Treatment with two of these three interventions does not significantly enhance the degree of axonal regeneration. In contrast, triple therapy combining NgR1 decoy, ChABC and preconditioning, allows axons to regenerate millimeters past the spinal cord injury site. The benefit of a pre-conditioning injury is most robust, but a peripheral nerve injury coincident with, or 3 days after, spinal cord injury also synergizes with NgR1 decoy and ChABC. Thus, maximal axonal regeneration and neural repair are achieved by combining independently effective pharmacological approaches.
已经确定了几种促进中枢神经系统损伤后神经修复和恢复的药理学方法。阻断星形胶质细胞衍生的软骨素硫酸盐蛋白聚糖（CSPGs）或少突胶质细胞衍生的 Nogo 受体（NgR1）配体可减少轴突生长的外在抑制，尽管尚未测试这些不同途径的联合阻断。几种途径可以促进成年哺乳动物神经元的内在生长潜力，包括背根神经节（DRG）神经元的预处理损伤和视网膜神经节细胞（RGC）的巨噬细胞激活。单从药理学干预来看，在没有外源细胞、机械支架或病毒基因治疗的情况下，其疗效有限。在这里，我们检查了药理学方法的组合，并评估了轴突再生的程度。在小鼠视神经挤压损伤后，NgR1-/-神经元再生 RGC 轴突的程度与佐剂型注射、巨噬细胞激活的 WT 小鼠一样广泛。在佐剂型注射的 NgR1-/-小鼠中，将这些干预措施结合起来可以实现协同增强再生。在大鼠脊髓背柱挤压损伤模型中，预处理外周坐骨神经轴突切断术、NgR1(310)外显子-Fc 诱饵蛋白治疗或软骨素酶 ABC（ChABC）治疗均可独立支持上行初级传入纤维在损伤部位附近再生到相似程度。用其中两种方法治疗并不能显著提高轴突再生的程度。相比之下，联合使用 NgR1 诱饵、ChABC 和预处理的三重疗法可使轴突再生数毫米，超过脊髓损伤部位。预处理损伤的益处最为显著，但脊髓损伤同时或 3 天后发生的外周神经损伤也与 NgR1 诱饵和 ChABC 协同作用。因此，通过组合独立有效的药理学方法可以实现最大程度的轴突再生和神经修复。
