PATHOGENESIS OF TOXIC AND METABOLIC NEUROPATHIES

实验性糖尿病神经病变的病理可分为 早期以运动神经传导速度减慢为特征， 神经纤维直径减小和与之相关的晚期变化 有髓神经纤维变性、丢失和微血管病变。至 解释早期的变化，在诱导后的几周内发生 糖尿病链脲佐菌素，我们建议增加葡萄糖和山梨醇 引起渗透和电解质紊乱，影响神经传导 而后期的变化(1-2年)可能主要归因于 小血管管壁增厚引起的缺血 (微血管病变)和血液粘度增加， 这会减少神经血流量。为了检验第一个假设，我们将 用一种新技术测量神经内液电解质浓度 为此目的开发的，将这些发现与化学物质， 电生理和形态参数。自早期糖尿病以来 影响神经间质，神经膜积液分析 山梨醇和白蛋白浓度是检测变化所必需的 这会导致浮肿。糖尿病患者体内存在蛋白质的糖基化 组织并可能以两种方式影响神经；糖化白蛋白导致 贪婪的吞噬作用使其能够穿过血神经屏障并穿透 髓鞘的内神经细胞、糖基化可产生结构和 影响传导的功能变化。评估脑缺血 假设，我们已经开发了一种测量神经血流量的方法 适用于大鼠坐骨神经等小体积的非侵入性技术 很有胆量。通过将活体测量的神经血流量与 身体的形态分析，我们希望评估的意义 慢性糖尿病神经病变中的缺血。海绵体的形态研究 人类糖尿病神经将继续发生微血管病变，由此我们的 初步证据表明，这一独特的解剖结构 神经供血使血管狭窄进一步复杂化 内皮细胞增殖，基底板增厚。通过协调 新的实验技术和已有的研究方法 神经病变，我们希望了解新陈代谢和血管的变化 间隙微环境相互作用，导致复杂的改变 功能和结构称为糖尿病神经病变。

The pathology of experimental diabetic neuropathy can be divided into an early phase characterized by reduced motor nerve conduction velocity, reduction in diameter of nerve fibers and late changes associated with degeneration and loss of myelinated nerve fibers and microangiopathy. To explain early changes, occurring within weeks of induction of streptozotocin diabetes, we suggest that increased glucose and sorbitol induce osmotic and electrolyte disturbances which affect nerve conduction while the late changes (1-2 years) may be substantially attributable to ischemia caused by thickening of walls of small blood vessels (microangiopathy) and increased blood viscosity, the combined effects of which reduce nerve blood flow. To test the first hypothesis, we will measure endoneurial fluid electrolyte concentration with a new technique developed for this purpose, relating the findings to chemical, electrophysiologic and morphologic parameters. Since early diabetes affects the nerve interstitium, analysis of endoneurial fluid concentrations of sorbitol and albumin are necessary to detect changes which can produce edema. Glycosylation of proteins occurs in diabetic tissue and may affect the nerve in two ways; glycosylated albumin causes avid pinocytosis allowing it to cross the blood nerve barrier and penetrate the endoneurium, glycosylation of myelin may produce structural and functional changes affecting conduction. To evaluate the ischemic hypothesis, we have developed a method for measuring nerve blood flow by a non-invasive technique suitable for small volumes such as the rat sciatic nerve. By correlating in vivo measurements of nerve blood flow with postmortem morphologic analysis, we hope to assess the significance of the ischemia in chronic diabetic neuropathy. Morphologic studies of microangiopathy will be continued in human diabetic nerve, from which our preliminary evidence suggests that the unique anatomic configuration of nerve blood supply further complicates vascular narrowing due to endothelial proliferation and basal laminar thickening. By coordinating new experimental techniques with established methods for investigating neuropathy, we hope to understand how metabolic and vascular changes in the interstitial microenvironment interact, causing complex alterations of function and structure known as diabetic neuropathy.