Taurine and Painful Diabetic Neuropathy

牛磺酸与疼痛性糖尿病神经病

• 批准号: 6953028
• 负责人: MARTIN J STEVENS
• 金额: $ 33.57万
• 依托单位: UNIVERSITY OF BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-29 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6953028
• 关键词: analgesics; antioxidants; chronic pain; clinical research; clinical trials; combination chemotherapy; diabetes mellitus therapy; diabetic neuropathy; disabling disease; human subject; human therapy evaluation; nervous system disorder chemotherapy; nervous system regeneration; neuropathology; outcomes research; oxidative stress; patient oriented research; perception; quality of life; sensory thresholds; taurine; temperature

DESCRIPTION (provided by applicant): Taurine and Painful Diabetic Neuropathy Diabetic neuropathy (DN) commonly complicates diabetes and can lead to lower limb amputations. In diabetes, neuropathic pain reduces quality of life, contributes to depression, limits exercise and impairs metabolic control thereby contributing to excess cardiovascular risk. Currently there are no treatments for DN other than improved metabolic control and conventional treatment for painful neuropathy can be cardiotoxic and have low efficacy. The etiology of pain complicating diabetes is poorly understood but may result from dysfunction of pain signaling pathways at multiple levels including cutaneous nociceptors, afferent neurons and spinal and supraspinal pathways. Taurine is a ubiquitous a amino acid, which functions as an antioxidant, regulator of glucose sensitive signal transduction pathways and analgesic such that its depletion in diabetes may contribute to the development of DN and pain. We have identified taurine depletion in the peripheral nerve of diabetic rodents and shown that taurine repletion alleviates hyperalgesia and prevents nerve metabolic, vascular and functional deficits. This proposal extends these observations and aims to explore the ability of taurine treatment alone to decrease pain and in combination with D-L-a-lipoic acid to improve nerve structure and function in patients with DN. The overall hypothesis is that taurine depletion contributes to the development of painful DN. The rationale is based on: (a) evidence implicating oxidative stress, altered neuronal calcium signaling and neuronal hyperexcitability in the development of painful DN (b) the emerging role of taurine as an important endogenous antioxidant, calcium regulator, neurotrophin, modulator of neuronal hyperexcitability and analgesic and (c) our data implicating an important role for taurine depletion and oxidative stress in the pathogenesis of experimental DN. The experimental approach will be to utilize biochemical, electrophysiological and imaging techniques to test the following aims: 1. Determine whether neuropathic pain complicating diabetes can be ameliorated by therapy with taurine. 2. Determine whether nerve functional and structural deficits complicating diabetes can be ameliorated by combination therapy with taurine and D-L-a-Iipoic acid. These studies will test a novel mechanistically based therapeutic approach to a common disabling and often-refractory complication of diabetes.

描述（由申请人提供）： 牛磺酸与疼痛性糖尿病神经病变 糖尿病神经病变（DN）通常使糖尿病并发症，并可导致下肢截肢。在糖尿病中，神经性疼痛降低生活质量，导致抑郁，限制运动并损害代谢控制，从而导致过度的心血管风险。目前，除了改善代谢控制外，没有其他治疗DN的方法，而疼痛性神经病的常规治疗可能具有心脏毒性，疗效较低。糖尿病并发疼痛的病因尚不清楚，但可能是由于多个水平的疼痛信号通路功能障碍，包括皮肤伤害感受器，传入神经元和脊髓和脊髓上通路。牛磺酸是一种普遍存在的α氨基酸，其作为抗氧化剂、葡萄糖敏感性信号转导途径的调节剂和镇痛剂发挥作用，使得其在糖尿病中的消耗可能有助于DN和疼痛的发展。我们已经确定了糖尿病啮齿动物外周神经中的牛磺酸耗竭，并表明牛磺酸补充可减轻痛觉过敏，防止神经代谢，血管和功能缺陷。该提案扩展了这些观察结果，旨在探索单独使用牛磺酸治疗减轻疼痛以及与D-L-α-硫辛酸联合使用改善DN患者神经结构和功能的能力。总的假设是，牛磺酸消耗有助于疼痛性DN的发展。理由基于：（a）证据表明氧化应激、改变的神经元钙信号传导和神经元超兴奋性在疼痛性DN的发展中起作用（B）牛磺酸作为重要的内源性抗氧化剂、钙调节剂、神经营养因子、神经元超兴奋性调节剂和镇痛剂的新作用和（c）我们的数据表明牛磺酸耗竭和氧化应激在实验性DN的发病机制中起重要作用。 实验方法将是利用生物化学、电生理学和成像技术来测试以下目标： 1.确定牛磺酸治疗是否可以改善糖尿病并发神经病理性疼痛。 2.确定牛磺酸和D-L-α-硫辛酸联合治疗是否可以改善糖尿病并发的神经功能和结构缺陷。这些研究将测试一种新的基于机制的治疗方法，以治疗糖尿病常见的致残性和难治性并发症。