Ischemic Paraplegia: Modulation by Stem Cell Implant

描述(申请人提供)：使用大鼠脊髓缺血模型，我们 已经表明，短暂性脊髓缺血的特定间隔会导致 大鼠中、小抑制性神经元的选择性变性 腰椎节段和明显的痉挛截瘫的发展。 胸腹主动脉手术患者的类似神经功能障碍 动脉瘤修复术已有报道。而神经元变性的程度 可部分受缺血周围温度和/或 曾经有大量脊髓神经元的药物治疗是 一旦失去，由此导致的神经缺陷是永久性的和不可逆转的。 重要的是，与脊柱机械损伤导致的截瘫相比， 其特征是部分或完全丧失降行道的完整性 在缺血诱导的截瘫后，下行系统显示出长期的存活。 这些特征指向了一种简单的去抑制机制 对于痉挛截瘫的存在。近年来，人们对此给予了极大的关注 一直专注于神经干细胞的潜在作用或培养 分化神经元及其改善治疗潜能的研究进展 脑或脊髓神经元后的神经功能障碍 神经变性/损伤。这些初步研究清楚地表明，椎管内 或脑内移植神经前体细胞或神经元有好处 不同病理性侮辱对功能恢复的影响 包括创伤或脑缺血。在目前的研究中，使用大鼠模型 我们将探讨脊椎动脉闭塞的可能治疗潜力 植入的神经前体细胞或分化的神经元 痉挛性截瘫动物运动功能的恢复。此外, 这些实验有助于揭示：一)人类的命运和分化 短暂缺血后脊髓移植干细胞或神经元，以及，ii) 生长因子(神经营养因子-3[NT-3]，脑源性)的特性 神经营养因子、胶质细胞源性神经营养因子 这可能会调节植入细胞的存活率以及局部 移植细胞和宿主神经元之间的突触发生。从一个实用的 立场，这些研究将系统地解决我们认为 具有基础和临床重要性。因此，替代神经元的能力 选择性地在脊髓缺血后丢失的池，并调节其 宿主组织中的功能整合可能被证明是特殊的 开发新的治疗模式对管理的意义 脊髓缺血引起的截瘫。

DESCRIPTION (provided by applicant): Using the rat spinal ischemia model, we have shown that specific intervals of transient spinal ischemia lead to a selective degeneration of small and medium-sized inhibitory neurons in lumbosacral segments and the development of prominent spastic paraplegia. Comparable neurological deficit in patients undergoing thoracoabdominal aortic aneurysm repair has been described. While the extent of neuronal degeneration can partially be manipulated by peri-ischemic temperature and/or pharmacological treatment once a significant population of spinal neurons is lost, the resulting neurological deficit is permanent and irreversible. Importantly, in contrast to spinal mechanical injury-induced paraplegia, which is characterized by a partial or complete loss of descending tracts integrity after ischemia-induced paraplegia, descending systems show long-term survival. These characteristics point into a simple disinhibitory mechanism accounting for the presence of spastic paraplegia. In recent years a significant attention has been focused on a potential role of neuronal stem cells or cultured differentiated neurons and their therapeutic potentials in ameliorating neurological dysfunction after brain or spinal neuronal neurodegeneration/injury. These initial studies clearly show that intraspinal or intracerebral grafting of neuronal progenitors or neurons have a beneficial effect on recovery of function after a variety of pathological insults including trauma or ischemia. In the present studies, using a rat model of aortic occlusion, we will examine a possible therapeutic potential of spinally implanted neuronal progenitors or differentiated neurons as assessed by the recovery of motor function in animals with spastic paraplegia. In addition, these experiments serve to shed light upon: i) the fate and differentiation of spinally implanted stem cells or neurons after transient ischemia, and, ii) characterization of growth factors (neurotrophin-3 [NT-3], brain-derived neurotrophic factor [BDNF], glial cell line-derived neurotrophic factor [GDNF]) that may modulate survivability of implanted cells as well as local synaptogenesis between implanted cells and host neurons. From a practical standpoint, these studies will systematically address issues which we believe have both basic and clinical importance. Thus, the ability to replace neuronal pools selectively that were lost after spinal ischemia and modulate their functional incorporation in the host tissue may prove to be of particular significance in developing novel therapeutic modalities for managing spinal-ischemia-induced paraplegia.