PATHOGENESIS OF TOXIC AND METABOLIC NEUROPATHIES

毒性和代谢性神经病的发病机制

• 批准号: 3395447
• 负责人: HENRY C. POWELL
• 金额: $ 18.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-12-01 至 1992-12-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3395447
• 关键词: L iditol dehydrogenase; Schwann cells; aldehyde reductase; autoimmune disorder; autoradiography; computer graphics /printing; diabetes mellitus therapy; diabetic angiopathy; diabetic neuropathy; disease /disorder model; drug related diabetes mellitus; electrolytes; electron microscopy; electron probe spectrometry; electrophysiology; galactose; galactosemias; gas chromatography; glucose transport; histochemistry /cytochemistry; hyperglycemia; hypoxia; insulin; ion transport; ischemia; laboratory rat; microcirculation; microelectrodes; myelinopathy; neural conduction; neural degeneration; oxidoreductase inhibitor; oxygen tension; peripheral nervous system disorders; radiotracer; sodium; sorbitol; streptozotocin; tissue /cell preparation; vascular endothelium permeability

The neurological consequences of diabetes exclusively affect the peripheral nervous system (PNS) and are linked to hypermetabolic activity in the sorbitol pathway and intrinsic microvascular changes which have long-term structural consequences. Hyperglycemia is the underlying defect and since nerves are insulin-independent, excess glucose enters the endoneurium being converted into osmotically active polyols. Transport mechanisms which convey hexoses across the blood-nerve barrier also carry sodium into the endoneurium resulting in increased osmotic activity associated with reduced nerve conduction velocity and reduced nerve fiber diameter in the early metabolic phase, during which neuropathy is most amenable to treatment with aldose reductase inhibitors and insulin. Our studies focus i) on the link between increased sodium and electrophysiologic disturbances, ii) fine structural localization of increased sodium in the axon and paranodal region and iii) mechanisms of glycogen accumulation in diabetic axons. In the latter stages of the disease microcirculatory changes become established and have an impact on the nerve fiber in which axonal degeneration and demyelination occur. Microangiopathy, resulting in narrowing of the capillaries, is implicated and the proposed research attaches particular significance to the transperineurial microcirculation which may play a key role in the pathogenesis of endoneurial ischemia. Both hyperglycemia and hypoxia are underlying mechanisms whose contributions to pathogenesis will be individually investigated using new techniques for measurement of nerve blood flow, endoneurial electrolyte analysis by x-ray microprobe, nerve oxygen tension and endoneurial fluid pressure. Biophysical techniques designed to investigate disturbances in the endoneurial microenvironment will be combined with classic morphologic and morphometric methods to determine the pathogenesis of the early changes in diabetic neuropathy knowledge of whose onset is crucial to initiate appropriate treatment before irreversible neuropathic changes supervene.

糖尿病的神经学后果只影响 周围神经系统（PNS），并与高代谢有关 山梨醇途径和内在微血管活性 这些变化具有长期的结构性影响。 过度兴奋是潜在的缺陷，由于神经 非胰岛素依赖性的过量葡萄糖进入神经内膜， 转化成具有药理活性的多元醇。 传输机制 它将己糖传送穿过血神经屏障， 钠进入神经内膜，导致渗透压增加 与神经传导速度降低相关的活动， 在早期代谢阶段神经纤维直径减少， 哪种神经病最适合用醛糖治疗 还原酶抑制剂和胰岛素。 我们的研究集中在i）联系 钠增加与电生理紊乱之间的关系，ii） 轴突中增加的钠的精细结构定位， 结旁区和iii）糖原积累的机制， 糖尿病轴突 在疾病的后期 微循环改变形成并产生影响 轴突变性和脱髓鞘的神经纤维 发生. 微血管病，导致毛细血管狭窄， 是牵连和拟议的研究重视特别是 对经神经束膜微循环的意义， 在神经内膜缺血的发病机制中起关键作用。 两 高血糖症和缺氧是潜在的机制， 对发病机制的贡献将单独研究 使用新技术测量神经血流， 用x线微探针分析神经内膜电解质，神经 氧分压和神经内膜压力。 生物物理 旨在研究神经内膜紊乱的技术 微环境将与经典的形态学和 形态测量方法来确定早期的发病机制， 糖尿病神经病变发病知识的变化 关键是在不可逆转之前开始适当的治疗 神经病变随之发生。