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）：神经病变是糖尿病的一种破坏性并发症。虽然传统的药物治疗可以减轻糖尿病神经病变的发展，但许多患者很难实现完美的血糖控制，因此需要额外的治疗选择。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（例如节段性脱髓鞘和轴突变性）之间的联系仍然未知。氧化应激与糖尿病神经病变的发病机制有关，最近提出线粒体电子传递链过量产生超氧化物是连接多元醇途径通量、AGE 形成、PKC 激活和己糖胺途径通量的共同因素，作为高血糖诱导的机制损害。由于几乎没有直接证据支持氧化应激是早期代谢事件与随后的结构损伤之间的联系，因此该提议的基本假设是糖尿病神经病变中无髓鞘和有髓纤维的结构损伤是高血糖诱导的氧化应激和线粒体损伤的最终结果。雪旺细胞和神经元功能障碍。这一假设的推论是，用适当的抗氧化剂和/或恢复线粒体功能的药物治疗将改善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测试，该模型复制人类糖尿病神经病变中存在的无髓鞘和有髓纤维的损伤。将使用行为学方法研究链脲佐菌素糖尿病大鼠和小鼠的表皮内神经支配变性、链脲佐菌素糖尿病大鼠坐骨神经和神经根的雪旺细胞损伤以及自发性糖尿病猫的腓神经活检中的脱髓鞘和轴突变性。 、电生理学、生化和组织学评估结合适当的治疗，以减轻氧化应激和线粒体功能障碍。使用这些糖尿病神经损伤的实验和临床动物模型，三个具体目标将确定 1) 表皮内神经支配丧失 2) 雪旺损伤和 3) 脱髓鞘和轴突变性是否是氧化应激和线粒体功能障碍的后果。