DEMYELINATION IN SPINAL CORD TRAUMA

脊髓创伤中的脱髓鞘

• 批准号: 3401936
• 负责人: ANDREW R BLIGHT
• 金额: $ 13.05万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-01 至 1995-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3401936
• 关键词: behavior test; biological models; chemotherapy; drug screening /evaluation; electrophysiology; guinea pigs; histopathology; inflammation; leukocytes; methylprednisolone; myelinopathy; nervous system regeneration; neuropharmacology; nonhuman therapy evaluation; silicates; spinal cord injury

The overall goal of this project is to advance understanding of the roles and interrelationships of inflammatory responses, demyelination, and axonal conduction block in the loss of function that follows traumatic injury to the spinal cord. This goal is directly relevant to the profound medical problems of treating acute and chronic spinal cord injury. A recent clinical trial has shown limited, but significant improvement in neurological outcome from spinal trauma, using very high doses of methylprednisolone within 8 hours of injury. However, it is still uncertain how this drug achieves its benefit, and it is difficult to identify and develop other effective treatments while the mechanisms of secondary pathological damage remain poorly understood. The present experiments will concentrate on the possible role of inflammatory responses in such secondary pathology. Pairwise-randomized, blinded experiments will be performed to examine the effects of intraperitoneal injections of silica dust (a macrophage toxin) on inflammatory responses and on functional and histological outcome from focal trauma. Injuries of the lower thoracic spinal cord will be produced in anesthetized adult guinea pigs, using a technique of compression that results in injuries of moderate severity. The outcome from injury will be monitored with behavioral tests, daily during the first week and weekly thereafter for up to three months. Animals will then be fixed for histological examination of the spinal cord in plastic sections (1 micromole) stained with toluidine blue. Quantitative morphometric sampling of myelinated axons and microvasculature will be performed in sections from the center of the lesion and from surrounding areas of the cord that experience axonal degeneration but little direct mechanical damage. Measures of functional change will be related to the quantitative morphometry of myelinated axons and vasculature in the chronic lesion and compared between experimental and control groups. Effects of silica injections on the inflammatory response will be examined in separate experiments in which the animals will be fixed for histology at 1, 2, 4, 8, or 14 days after injury. Effects of silica injections on the development of the inflammatory response will be related to the timing of effects on the secondary loss of behavioral and electrophysiological function, and to changes in circulating leukocytes. Similar techniques of injury and quantitative analysis will than be used to examine whether neurological outcome in the guinea pig model is improved by methylprednisolone (30 mg/kg i.v. bolus beginning at 45 minutes post injury) and whether any improvement is related to a particular histological change or a particular time in the evolution of secondary pathological events in the spinal cord, particularly that associated with the peak of phagocytic activity.

该项目的总体目标是提高对角色的理解 以及炎症反应，脱髓鞘和 轴突传导阻滞在造成创伤之后的功能丧失中 脊髓损伤。 这个目标与 治疗急性和慢性脊髓的深刻医学问题 受伤。 最近的一项临床试验显示有限但很重要 使用非常高的脊柱创伤改善神经系统结局 受伤后的8小时内，甲基强酮的剂量。 但是，是 仍然不确定这种药物如何实现其好处，这很困难 识别和开发其他有效的治疗方法 继发性病理损害的理解仍然很差。 现在 实验将集中于炎症的可能作用 这种次要病理的反应。 将进行成对随机的盲实验，以检查 腹膜内注射二氧化硅灰尘（巨噬细胞毒素）的影响 关于炎症反应以及功能和组织学结果 局部创伤。 下胸脊髓的伤害将是 用麻醉的成年豚鼠生产 压缩导致严重程度中等的伤害。 结果 每天在 此后的第一周和每周最多三个月。 动物会 然后固定以进行塑料中脊髓的组织学检查 用甲苯胺蓝色染色的切片（1微米）。 定量 髓鞘轴突和微脉管系统的形态计量学采样将是 在病变中心和周围的部分中进行 脐带的区域经历了轴突变性，但几乎没有直接 机械损坏。 功能变化的度量将与 髓鞘轴突和脉管系统的定量形态计量学 慢性病变并在实验组和对照组之间进行比较。 二氧化硅注射对炎症反应的影响将是 在单独的实验中检查了动物的固定 受伤后1、2、4、8或14天的组织学。 二氧化硅的影响 关于炎症反应发展的注射将是 与对行为的继发性丧失和行为丧失的影响有关 电生理功能，以及循环白细胞的变化。 相似的伤害和定量分析技术将比使用 检查豚鼠模型中的神经系统结果是否是 通过甲基prednisolone改进（30 mg/kg i.v. los始于45 受伤后分钟）以及是否有任何改进与 特定的组织学变化或特定时间 脊髓中的次要病理事件，特别是 与吞噬活性的峰有关。