Bunge Mary Bartlett
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida 33101, USA.
J Spinal Cord Med. 2008;31(3):262-9. doi: 10.1080/10790268.2008.11760720.
Due to the varied and numerous changes in spinal cord tissue following injury, successful treatment for repair may involve strategies combining neuroprotection (pharmacological prevention of some of the damaging intracellular cascades that lead to secondary tissue loss), axonal regeneration promotion (cell transplantation, genetic engineering to increase growth factors, neutralization of inhibitory factors, reduction in scar formation), and rehabilitation. Our goal has been to find effective combination strategies to improve outcome after injury to the adult rat thoracic spinal cord. Combination interventions tested have been implantation of Schwann cells (SCs) plus neuroprotective agents and growth factors administered in various ways, olfactory ensheathing cell (OEC) implantation, chondroitinase addition, or elevation of cyclic AMP. The most efficacious strategy in our hands for the acute complete transection/SC bridge model, including improvement in locomotion [Basso, Beattie, Bresnahan Scale (BBB)], is the combination of SCs, OECs, and chondroitinase administration (BBB 2.1 vs 6.6, 3 times more myelinated axons in the SC bridge, increased serotonergic axons in the bridge and beyond, and significant correlation between the number of bridge myelinated axons and functional improvement). We found the most successful combination strategy for a subacute spinal cord contusion injury (12.5-mm, 10-g weight, MASCIS impactor) to be SCs and elevation of cyclic AMP (BBB 10.4 vs 15, significant increases in white matter sparing, in myelinated axons in the implant, and in responding reticular formation and red and raphe nuclei, and a significant correlation between the number of serotonergic fibers and improvement in locomotion). Thus, in two injury paradigms, these combination strategies as well as others studied in our laboratory have been found to be more effective than SCs alone and suggest ways in which clinical application may be developed.
由于脊髓损伤后脊髓组织会发生各种各样且数量众多的变化，成功的修复治疗可能需要综合运用多种策略，包括神经保护（通过药物预防一些导致继发性组织损失的有害细胞内级联反应）、促进轴突再生（细胞移植、基因工程以增加生长因子、中和抑制因子、减少瘢痕形成）以及康复治疗。我们的目标是找到有效的联合策略，以改善成年大鼠胸段脊髓损伤后的预后。所测试的联合干预措施包括施万细胞（SCs）植入加以各种方式给药的神经保护剂和生长因子、嗅鞘细胞（OEC）植入、添加软骨素酶或提高环磷酸腺苷水平。在我们手中，对于急性完全横断/SC桥接模型，最有效的策略（包括运动功能改善[巴索、比蒂、布雷斯纳汉评分（BBB）]）是联合施用SCs、OECs和软骨素酶（BBB评分从2.1提高到6.6，SC桥接处有髓轴突数量增加3倍，桥接处及以外区域5-羟色胺能轴突增加，且桥接处有髓轴突数量与功能改善之间存在显著相关性）。我们发现，对于亚急性脊髓挫伤损伤（12.5毫米，10克重量，MASCIS撞击器），最成功的联合策略是SCs和提高环磷酸腺苷水平（BBB评分从10.4提高到15，白质保留、植入物中有髓轴突、反应性网状结构以及红核和中缝核均有显著增加，且5-羟色胺能纤维数量与运动功能改善之间存在显著相关性）。因此，在两种损伤模式中，这些联合策略以及我们实验室研究的其他策略已被证明比单独使用SCs更有效，并为临床应用的开发提供了思路。
