PATHOGENESIS OF TOXIC AND METABOLIC NEUROPATHIES

实验性糖尿病神经病变的病理学可分为 早期以运动神经传导速度降低为特征， 神经纤维直径的减少和与之相关的晚期变化 有髓神经纤维变性和丢失以及微血管病。 到 解释早期变化，发生在诱导后几周内， 链脲佐菌素糖尿病，我们认为，增加葡萄糖和山梨醇， 引起影响神经传导渗透和电解质紊乱 虽然后期变化（1-2年）可能主要归因于 由于小血管壁增厚而引起的局部缺血 （微血管病）和血液粘度增加， 从而减少神经血流量。 为了验证第一个假设，我们将 一种新的神经内液电解质浓度测定方法 为此目的而开发，将研究结果与化学， 电生理和形态学参数。 由于早期糖尿病 影响神经鞘，神经内膜液分析 山梨醇和白蛋白的浓度是检测变化所必需的 从而导致水肿。 糖基化蛋白发生在糖尿病 组织，并可能以两种方式影响神经;糖基化白蛋白导致 积极的胞饮作用使其能够穿过血神经屏障并穿透 在神经内膜中，髓鞘的糖基化可以产生结构和 影响传导的功能变化。 评估缺血性 假设，我们已经开发了一种方法，用于测量神经血流量的一个 非侵入性技术适用于小体积，如大鼠坐骨神经 神经。 通过将神经血流量的体内测量与 死后形态学分析，我们希望评估的意义， 慢性糖尿病性神经病变中局部缺血 的形态学研究 微血管病变将继续在人类糖尿病神经，从我们的 初步证据表明，独特的解剖结构， 神经血液供应进一步使血管狭窄复杂化， 内皮细胞增生和基底层增厚。 通过协调 新的实验技术和既定的研究方法 神经病变，我们希望了解如何代谢和血管的变化， 间质微环境相互作用，导致 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.