PATHOGENESIS OF TOXIC AND METABOLIC NEUROPATHIES

糖尿病引起的周围神经病变是最常见的 与糖尿病相关的并发症和最常见的 这个国家的神经病。然而，虽然高血糖一直是 在发病机制中被认为是基本的代谢紊乱 代谢事件与糖尿病神经病变的关系 随后的结构性变化仍不明朗。以前的工作已经表明 高血糖诱导的夸大的多元醇途径流量是 中国人周围神经生化和功能障碍的数量 实验性糖尿病，以及最近，它与 轴突萎缩、雪旺细胞变性等结构改变 可能导致轴索病变和节段性脱髓鞘的改变。 阐明了被夸大的多元醇途径活性和 结构性变化是这项研究的广泛、长期目标。 求婚。这些研究将在三个最好的- 实验性高血糖大鼠模型：链脲佐菌素诱导 糖尿病、半乳糖中毒与遗传性糖尿病BB/Wistar 老鼠。植物体内的第一种酶--醛糖还原酶的定位 通往雪旺细胞的多元醇途径表明，这种干扰 细胞功能可能是原发病变。的结构完整性 雪旺细胞和神经的其他细胞成分 将对微环境进行定性和定量的考察 横跨雪旺细胞起始时间点的电子显微镜观察 损伤和继发性轴突变性与醛糖的评估 用酶法和凝胶电泳法测定还原酶含量。此外，AS 不断积累的证据暗示了连续施万恩的必要性 细胞-轴突相互作用，雪旺细胞衍生的嗜神经细胞水平 睫状神经营养因子将用一种 施万氏病发病前和发病后各时间点的微生物检测 细胞结构受损。生理学和生理学的时间序列 神经微环境中的生化变化将被表征 通过关联神经传导速度，作为功能性的指标 神经内液电解质、多元醇和水的损害 用电生理、能量色散光谱和气体分析测定含量 层析法。因为轴突损伤也可能是多元醇途径- 通过血-神经屏障通透性改变和减少而引起的变化 神经血液流动，测定渗透性的活体示踪法- 表面积产品和神经血流量将在适当的时候使用 时间点。所有研究都将包括醛糖还原酶抑制剂的治疗 评估多元醇途径在神经疾病中的作用的小组。 因此，这项研究方案将综合形态、生理和 糖尿病病理生理学研究中的生化技术 神经病。

Diabetes-induced peripheral neuropathy is the most common of the complications associated with diabetes mellitus and the most prevalent neuropathy in the country. However, while hyperglycemia has been identified as the fundamental metabolic disturbance in the pathogenesis of diabetic neuropathy, the relationship between metabolic events and subsequent structural changes remains unclear. Previous work has shown that hyperglycemia-induced exaggerated polyol pathway flux underlies a number of biochemical and functional disorders of peripheral nerve in experimental diabetes and more recently, that it is associated with structural changes such as axonal dwindling and degenerative Schwann cell changes that may lead to axonopathy and segmental demyelination. Elucidating the link between exaggerated polyol pathway activity, and structural changes is the broad, long-term objective of this research proposal. These studies will be performed in three of the best- characterized rat models of hyperglycemia: streptozotocin induced diabetes, galactose intoxication and the genetically diabetic BB/Wistar rat. The localization of aldose reductase, the first enzyme of the polyol pathway, to the Schwann cell suggests that disruption of this cell's function may be the primary lesion. The structural integrity of the Schwann cell and other cellular elements of the nerve microenvironment will be examined by qualitative and quantitative electron microscopy at time points that span the onset of Schwann cell damage and subsequent axonal degeneration along with evaluation of aldose reductase content by enzyme assay and gel electrophoresis. Also, as accumulating evidence implicates the necessity of continuous Schwann cell-axon interaction, levels of the Schwann cell-derived neuronotropic factor, ciliary neuronotrophic factor, will be assayed with a microbioassay at time points prior to and including the onset of Schwann cell structural damage. The temporal sequence of physiologic and biochemical changes in the nerve microenvironment will be characterized by correlating nerve conduction velocity, as an index of functional impairment, with endoneurial fluid electrolytes, polyols and water content using electrophysiology, energy dispersive spectrometry and gas chromatography. As axonal damage may also result from polyol-pathway- induced changes via altered blood-nerve barrier permeability and reduced nerve blood flow, in vivo tracer methods for determining permeability- surface area products and nerve blood flow will be used at appropriate time points. All studies will include aldose reductase inhibitor treated groups to assess the role of the polyol pathway in nerve disorders. Thus, this research proposal, will integrate morphologic, physiologic and biochemical techniques to study the pathophysiology of diabetic neuropathy.