Davies Jeannette E, Tang Xiufeng, Bournat Juan C, Davies Stephen J A
Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA.
J Neurotrauma. 2006 Mar-Apr;23(3-4):397-408. doi: 10.1089/neu.2006.23.397.
Spinal cord scar tissue presents a combined physical and molecular barrier to axon regeneration. Theoretically, spinal cord injuries (SCIs) can be rendered more permissive to axon growth by either suppressing synthesis of misaligned, fibrotic scar tissue and associated axon growth inhibitors, or enzymatically degrading them. We have previously shown that acute infusion of human recombinant decorin core protein into discreet stab injuries of the rat dorsal column pathways effected a major suppression of inflammation, astrogliosis, and multiple axon growth inhibitory chondroitin sulfate proteoglycans, which combined to promote rapid axon growth across the injury site. The high efficiency of chondroitin sulfate proteoglycan (CSPG) core protein suppression (approximately 90%) suggested that decorin may promote CSPG degradation in addition to suppressing CSPG synthesis. As the serine protease plasmin can degrade axon growth inhibitory CSPGs (neurocan and phosphacan) and its zymogen, plasmininogen is synthesized by microglia, we have investigated whether decorin treatment of acute SCIs and cultured adult spinal cord microglia can increase plasminogen/ plasmin synthesis. Infusion of hr-decorin over the first 8 days post-SCI induced 10- and 17-fold increases in plasminogen and plasmin protein levels, respectively, within sites of injury and a threefold increase in microglial plasminogen mRNA in vitro. In addition to potentially degrading multiple axon growth inhibitory components of the glial scar, plasmin is known to play major roles in activating neurotrophins and promoting central nervous system (CNS) plasticity. The wider implications of decorin induction of plasmin in the injured spinal cord for axon regeneration, and recovery of function at acute and chronic time points post-SCI are reviewed.
脊髓瘢痕组织对轴突再生构成了物理和分子双重障碍。从理论上讲，通过抑制排列紊乱的纤维化瘢痕组织及相关轴突生长抑制因子的合成，或通过酶促降解这些物质，可使脊髓损伤（SCI）对轴突生长更具容许性。我们之前已经表明，将人重组核心蛋白聚糖急性注入大鼠背柱通路的离散刺伤部位，可显著抑制炎症、星形胶质细胞增生以及多种轴突生长抑制性硫酸软骨素蛋白聚糖，这些作用共同促进了轴突快速穿过损伤部位生长。硫酸软骨素蛋白聚糖（CSPG）核心蛋白抑制效率很高（约90%），这表明核心蛋白聚糖除了抑制CSPG合成外，可能还促进了CSPG降解。由于丝氨酸蛋白酶纤溶酶可降解轴突生长抑制性CSPG（神经黏蛋白和磷黏蛋白），且其酶原纤溶酶原由小胶质细胞合成，我们研究了核心蛋白聚糖治疗急性脊髓损伤以及培养的成年脊髓小胶质细胞是否能增加纤溶酶原/纤溶酶的合成。在脊髓损伤后的头8天内注入hr-核心蛋白聚糖，分别使损伤部位的纤溶酶原和纤溶酶蛋白水平增加了10倍和17倍，并且在体外使小胶质细胞纤溶酶原mRNA增加了3倍。除了可能降解胶质瘢痕中多种轴突生长抑制成分外，已知纤溶酶在激活神经营养因子和促进中枢神经系统（CNS）可塑性方面也发挥着重要作用。本文综述了核心蛋白聚糖在损伤脊髓中诱导纤溶酶对轴突再生以及脊髓损伤后急性和慢性时间点功能恢复的更广泛影响。
