Oxidative Stress and Nerve Pathology in Diabetes

糖尿病的氧化应激和神经病理学

• 批准号: 7142704
• 负责人: ANDREW P MIZISIN
• 金额: $ 28.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7142704
• 关键词: Schwann cells; axon; cats; diabetes mellitus; diabetic neuropathy; disease /disorder model; histology; hyperglycemia; innervation; laboratory mouse; laboratory rat; mitochondrial disease /disorder; myelinopathy; nerve injury; neural degeneration; neurons; neuropathology; oxidative stress; pathologic process

DESCRIPTION (provided by applicant): Neuropathy is a devastating complication of diabetes mellitus. While conventional medical treatment attenuates the development of diabetic neuropathy, perfect glycemic control is difficult to achieve in many patients and points to the need for additional therapeutic options. Although hyperglycemia has been identified as the primary metabolic disturbance underlying neurological complications, the link between early metabolic events and subsequent structural changes, such as segmental demyelination and axonal degeneration, remains unknown. Oxidative stress has been implicated in the pathogenesis of diabetic neuropathy and overproduction of superoxide by mitochondrial electron-transport chains has recently been proposed to be the common element linking polyol pathway flux, AGE formation, PKC activation and hexosamine pathway flux as mechanisms of hyperglycemia-induced damage. Because there is little direct evidence supporting oxidative stress as the link between early metabolic events and subsequent structural injury, the underlying hypothesis of this proposal presumes that structural injury of unmyelinated and myelinated fibers in diabetic neuropathy is the culmination of hyperglycemia-induced oxidative stress and mitochondrial dysfunction in Schwann cells and neurons. A corollary to this hypothesis is that treatment with appropriate anti-oxidants and/or agents that restore mitochondrial function will ameliorate pathological injury to these nerve fibers. The hypothesis will be tested using carefully selected animal models that replicate injury to unmyelinated and myelinated fibers present in human diabetic neuropathy. Degeneration of the intra-epidermal innervation in streptozotocin-diabetic rats and mice, Schwann cell injury in the sciatic nerve and roots of streptozotocin-diabetic rats, and demyelination and axonal degeneration in peroneal nerve biopsies from cats with spontaneously occurring diabetes will be investigated using behavioral, electrophysiological, biochemical and histological assessments in combination with appropriate treatments to alleviate oxidative stress and mitochondrial dysfunction. Using these experimental and clinical animal models of diabetic nerve injury, three specific aims will determine whether 1) loss of intra-epidermal innervation 2) Schwann injury, and 3) demyelination and axonal degeneration are consequences of oxidative stress and mitochondrial dysfunction.

描述（由申请人提供）：神经病是糖尿病的毁灭性并发症。尽管常规的医学治疗减轻了糖尿病神经病的发展，但在许多患者中很难实现完美的血糖控制，并指出需要其他治疗选择。尽管高血糖已被确定为神经系统并发症的主要代谢紊乱，但早期代谢事件与随后的结构变化之间的联系，例如节段性脱髓鞘和轴突变性，仍然未知。最近有人认为，通过线粒体电子传输链对糖尿病神经病的发病机理和超氧化物的过量产生，是连接多元途径通量，年龄形成，PKC活化和己糖胺途径的共同元素，作为超高诱导损害的机制。由于几乎没有直接证据支持氧化应激作为早期代谢事件与随后的结构损伤之间的联系，因此该提案的基本假设认为，糖尿病神经性无髓和髓鞘纤维的结构性损伤是高血糖诱导的氧化应激胁迫诱导的氧化应激和氧化型细胞的结构性。这一假设的推论是，恢复线粒体功能的适当抗氧化剂和/或药物的治疗将减轻对这些神经纤维的病理损伤。该假设将使用精心挑选的动物模型进行检验，这些模型复制了人类糖尿病神经病中存在的无髓和髓鞘纤维的损伤。链蛋白酶 - 糖尿病大鼠和小鼠的表皮内神经支配的退化，坐骨神经中的Schwann细胞损伤以及链蛋白酶 - 糖尿病 - 糖尿病性大鼠的根，以及使用自发性糖尿病的猫的厌氧和轴突变性，以及垂直神经活检中的糖尿病性，是糖尿病性的。结合适当的治疗方法，以减轻氧化应激和线粒体功能障碍。使用这些实验性和临床动物模型的糖尿病神经损伤，三个特定的目标将决定1）表皮内神经的丧失2）Schwann损伤，3）脱髓鞘和轴突变性是氧化应激和线粒体功能障碍的结果。