Prevention of Diabetic Neuropathy with ACE Inhibitors

使用 ACE 抑制剂预防糖尿病神经病变

基本信息

批准号：
8271438
负责人：
Mark A. Yorek
金额：
$ 26.24万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8271438
关键词：
3-nitrotyrosine Acetylcholine Address Adverse effects Angiotensin II Receptor Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Animal Model Antioxidants Attenuated Blood Vessels Blood flow Bradykinin C-Type Natriuretic Peptide Calcitonin Gene-Related Peptide Cardiovascular Diseases Clinical Clinical Research Clinical Trials Development Diabetes Mellitus Diabetic Neuropathies Dipeptidyl-Peptidase IV Disease Drug usage Enalapril Endothelium Enzyme Inhibition Epidermis Filament Functional disorder Future Goals Health Human Impairment Insulin-Dependent Diabetes Mellitus Kidney Diseases Knowledge Measurement Mediating Mediator of activation protein Metabolic syndrome Modeling Motor Natriuretic Peptides Neprilysin Nerve Nerve Fibers Neural Conduction Neuropathy Neuropeptides Nitric Oxide Nociception Non-Insulin-Dependent Diabetes Mellitus Obesity Oxidative Stress Patients Peptide Hydrolases Peptides Peptidyl-Dipeptidase A Peripheral Peripheral Vascular Diseases Peroxonitrite Pharmaceutical Preparations Pharmacodynamics Prediabetes syndrome Prevention Property Rat-1 Rattus Relaxation Research Role Streptozocin Superoxides Testing Tissues United States Vascular Endothelium-Dependent Relaxation Vasodilation Vasodilator Agents Work Zucker Rats afferent nerve arteriole base design diabetic diabetic rat effective therapy efficacy testing enzyme activity glucagon-like peptide improved inhibitor/antagonist insulin sensitivity novel strategies preclinical study prevent primary outcome relating to nervous system sciatic nerve secondary outcome therapy design type I and type II diabetes

项目摘要

DESCRIPTION (provided by applicant): The goal of our studies is to determine whether treatment of streptozotocin-induced diabetic rats, an animal model for type 1 diabetes, Zucker Diabetic Fatty (ZDF) rats, an animal model for type 2 diabetes, or Zucker obese rats, an animal model for pre-diabetes/metabolic syndrome with Enalapril, an angiotensin converting enzyme (ACE) inhibitor, AVE7688, a vasopeptidase inhibitor, or Sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, prevents/reverses the development/progression of diabetic neuropathy (DN). Treatment of diabetes patients with ACE inhibitors is a common form of treatment for renal and cardiovascular disease. However, there is a lack of knowledge about the potential benefits of ACE inhibitor treatment for DN. ACE inhibitors have been shown to have antioxidant and neuroprotective properties; whereas vasopeptidase inhibitors block both ACE and neutral endopeptidase (NEP) activity. We also have evidence that Sitagliptin, a drug used to increase insulin sensitivity and treat type 2 diabetes, may also inhibit NEP. NEP degrades natriuretic peptides as well as neuropeptides such as calcitonin gene-related peptide (CGRP) and bradykinin. Our working hypothesis is that vascular dysfunction contributes significantly to DN and that successful therapies for DN must protect the vasculature. We have shown that diabetes and obesity alters the activity of vasodilators in epineurial arterioles including nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and CGRP. This likely causes an impairment of blood flow to the nerve and contributes to DN. Based on recent studies we hypothesize the C-type natriuretic peptide (CNP) functions as EDHF in epineurial arterioles. CNP causes vasodilation of epineurial arterioles and CNP activity/expression is decreased by diabetes. Therefore, we propose that treating rat models of type 1 and type 2 diabetes as well as obesity with Enalapril, AVE7688 or Sitagliptin will attenuate the development/progression of DN by: 1) preventing oxidative stress in vascular tissue thereby protecting the activity of NO, 2) preventing the loss of CNP and protecting its bioactivity, and 3) protecting sensory nerves and the availability and function of CGRP. If successful, these studies could provide a rationale for designing clinical studies to further test the efficacy of ACE and/or vasopeptidase inhibitor treatment in human DN. PUBLIC HEALTH RELEVANCE: After many years of research that is not an effective treatment for diabetic neuropathy. The goal of this study is to test the efficacy in pre-clinical studies of three classes of drugs on diabetic vascular and neural disease. Our working hypothesis is that vascular dysfunction contributes significantly to diabetic neuropathy and that successful therapies must protect the vasculature. If successful, these studies could provide a rationale for designing clinical studies to further test the efficacy of angiotensin converting enzyme and/or vasopeptidase inhibitor treatment in human diabetic neuropathy.

描述（由申请人提供）：我们研究的目标是确定是否可以治疗链脲佐菌素诱导的糖尿病大鼠（1 型糖尿病动物模型）、Zucker 糖尿病脂肪 (ZDF) 大鼠（2 型糖尿病动物模型）或 Zucker肥胖大鼠，使用依那普利（一种血管紧张素转换酶（ACE）抑制剂）、AVE7688（一种血管肽酶抑制剂）建立的糖尿病前期/代谢综合征动物模型，或西格列汀，一种二肽基肽酶 IV (DPP-IV) 抑制剂，可预防/逆转糖尿病神经病变 (DN) 的发生/进展。用ACE抑制剂治疗糖尿病患者是治疗肾脏和心血管疾病的常见形式。然而，人们对 ACE 抑制剂治疗 DN 的潜在益处缺乏了解。 ACE 抑制剂已被证明具有抗氧化和神经保护特性；然而血管肽酶抑制剂可阻断 ACE 和中性肽链内切酶 (NEP) 活性。我们也有证据表明西格列汀（一种用于增加胰岛素敏感性和治疗 2 型糖尿病的药物）也可能抑制 NEP。 NEP 降解钠尿肽以及神经肽，例如降钙素基因相关肽 (CGRP) 和缓激肽。我们的工作假设是，血管功能障碍对 DN 有显着影响，并且成功的 DN 治疗必须保护脉管系统。我们已经证明，糖尿病和肥胖会改变神经外膜小动脉中血管扩张剂的活性，包括一氧化氮 (NO)、内皮源性超极化因子 (EDHF) 和 CGRP。这可能会导致神经血流受损并导致 DN。根据最近的研究，我们假设 C 型利钠肽 (CNP) 在神经外膜小动脉中发挥 EDHF 的作用。 CNP 引起神经外膜小动脉血管舒张，糖尿病会降低 CNP 活性/表达。因此，我们建议使用依那普利、AVE7688 或治疗 1 型和 2 型糖尿病以及肥胖症大鼠模型西他列汀将通过以下方式减轻 DN 的发生/进展： 1) 预防氧化应激在血管组织中，从而保护 NO 的活性，2）防止 CNP 的损失并保护其生物活性，3）保护感觉神经以及 CGRP 的可用性和功能。如果成功，这些研究可以为设计临床研究提供依据，以进一步测试 ACE 和/或血管肽酶抑制剂治疗人类 DN 的疗效。公众健康相关性：经过多年的研究，这并不是糖尿病神经病变的有效治疗方法。本研究的目的是测试三类药物对糖尿病血管和神经疾病的临床前研究的疗效。我们的工作假设是，血管功能障碍对糖尿病神经病变有显着影响，成功的治疗必须保护脉管系统。如果成功，这些研究可以为设计临床研究提供理论依据，以进一步测试血管紧张素转换酶和/或血管肽酶抑制剂治疗人类糖尿病神经病变的功效。