Prevention of Diabetic Neuropathy with ACE Inhibitors

描述（申请人提供）：我们研究的目的是确定用依那普利（一种血管紧张素转化酶（ACE）抑制剂）、AVE 7688（一种血管肽酶抑制剂）治疗链脲佐菌素诱导的糖尿病大鼠（一种1型糖尿病动物模型）、Zucker糖尿病肥胖（ZDF）大鼠（一种2型糖尿病动物模型）或Zucker肥胖大鼠（一种糖尿病前期/代谢综合征动物模型），或西他列汀，一种二肽基肽酶IV（DPP-IV）抑制剂，预防/逆转糖尿病神经病变（DN）的发展/进展。用ACE抑制剂治疗糖尿病患者是肾脏和心血管疾病的常见治疗形式。然而，对于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;而 血管肽酶抑制剂阻断ACE和中性内肽酶（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降解利钠肽以及降钙素基因相关肽（CGRP）和缓激肽等神经肽。我们的工作假设是，血管功能障碍有助于显着DN和DN的成功治疗必须保护血管。我们已经发现糖尿病和肥胖改变了神经外膜小动脉中血管舒张剂的活性，包括一氧化氮（NO）、内皮源性超极化因子（EDHF）和CGRP。这可能导致流向神经的血流受损并导致DN。基于最近的研究，我们假设C型利钠肽（CNP）在神经外膜小动脉中起EDHF的作用。CNP引起神经外膜小动脉的血管舒张，并且CNP活性/表达因糖尿病而降低。因此，我们建议， 用依那普利、AVE 7688或 西格列汀将通过以下方式减缓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，和3）保护感觉神经和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理论依据，以进一步测试ACE和/或血管肽酶抑制剂治疗人DN的疗效。公共卫生相关性：经过多年的研究，这不是一个有效的治疗糖尿病神经病变。本研究的目的是在临床前研究中测试三类药物对糖尿病血管和神经疾病的疗效。我们的工作假设是，血管功能障碍有助于显着糖尿病神经病变和成功的治疗必须保护血管。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疗效。

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.