PATHOGENESIS OF TOXIC AND METABOLIC NEUROPATHIES

毒性和代谢性神经病的发病机制

• 批准号: 2262606
• 负责人: HENRY C. POWELL
• 金额: $ 24.71万
• 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 1996-12-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2262606
• 关键词: L iditol dehydrogenase; Schwann cells; aldehyde reductase; axon; diabetic neuropathy; disease /disorder model; drug related diabetes mellitus; electron microscopy; electrophysiology; galactose; gas chromatography; gel electrophoresis; glucose transport; histochemistry /cytochemistry; histopathology; hyperglycemia; ion transport; ischemia; laboratory rat; lyophilization; microcirculation; myelinopathy; neural conduction; neural degeneration; neuronal transport; neurotrophic factors; peripheral nervous system disorders; sorbitol; spectrometry; tissue /cell preparation; vascular endothelium permeability; western blottings

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.

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， 国内的神经病。 然而，尽管高血糖症已经被 被确定为发病机制中的基本代谢紊乱 糖尿病神经病变，代谢事件之间的关系， 随后的结构变化仍不清楚。 以前的工作表明 高血糖诱导的过度多元醇途径通量是 周围神经生化和功能障碍的数量 实验性糖尿病，最近，它与 结构变化，如轴突萎缩和许旺细胞退化 可能导致轴突病和节段性脱髓鞘的变化。 阐明夸大的多元醇途径活性之间的联系， 结构变化是本研究的广泛、长期目标 提议 这些研究将在三个最好的- 特征性高血糖大鼠模型：链脲佐菌素诱导 糖尿病、半乳糖中毒和遗传性糖尿病BB/Wistar 大鼠 醛糖还原酶的定位， 多元醇途径，雪旺氏细胞表明，破坏这一点， 细胞功能受损可能是原发性病变。 的结构完整性 雪旺氏细胞和其他神经细胞 微环境将通过定性和定量研究 在跨越雪旺细胞发病的时间点进行电子显微镜检查 损伤和随后的轴突变性沿着评价醛糖 通过酶测定和凝胶电泳测定还原酶含量。 同样如 不断积累的证据暗示了连续施旺的必要性 细胞-轴突相互作用，雪旺细胞源性神经元亲 因子，睫状神经营养因子，将用 在雪旺氏病发作前和包括雪旺氏病发作在内的时间点进行微生物测定 细胞结构损伤。 生理和心理的时间顺序 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，作为功能指标， 损伤，伴有神经内膜液电解质、多元醇和水 内容使用电生理学，能量色散光谱和气体 层析 由于轴突损伤也可能由多元醇途径引起， 通过改变血-神经屏障通透性诱导变化， 神经血流量，用于测定渗透性的体内示踪剂方法， 表面积产品和神经血流量将在适当的时候使用 时间点。 所有研究均将纳入接受醛糖还原酶抑制剂治疗的患者 组，以评估多元醇通路在神经疾病中的作用。 因此，这项研究建议，将整合形态，生理和 研究糖尿病的病理生理学的生化技术 神经病变