Department of Veterans Affairs Iowa City Health Care System, University of Iowa, Iowa City, IA 52246, USA.
Neuropharmacology. 2011 Feb-Mar;60(2-3):259-66. doi: 10.1016/j.neuropharm.2010.09.008. Epub 2010 Sep 16.
Previously we demonstrated that inhibition of neutral endopeptidase (NEP), a protease that degrades vaso- and neuro-active peptides, and angiotensin converting enzyme (ACE) with a vasopeptidase inhibitor improves vascular and neural function in diabetic rat models. The purpose of this study was to determine whether inhibition of NEP and ACE or deletion of NEP provides protection from nerve impairment caused by diabetes or diet induced obesity (DIO). To determine the role of NEP and ACE inhibition in neuropathy related to insulin-deficient diabetes or DIO we used C57Bl/6J mice treated with AVE7688, a vasopeptidase inhibitor, or NEP deficient (-/-) mice. Mice at 12 weeks of age were fed a high fat diet for 12 weeks or were diabetic for duration of 12 weeks following a single injection of high dose streptozotocin. Both a prevention and intervention protocol was used for AVE7688 treatment. Glucose utilization was impaired in DIO C57Bl/6J and NEP -/- mice. However, treating DIO C57Bl/6J or NEP -/- mice with AVE7688 improved glucose tolerance. Thermal hypoalgesia and nerve conduction slowing were present in both streptozotocin-diabetic and DIO C57Bl/6J mice but not in AVE7688 treated C57Bl/6J mice or NEP -/- mice exposed to either streptozotocin-induced diabetes or a high fat diet. Intraepidermal nerve fiber (IENF) profiles were decreased in the hindpaw of C57Bl/6J diabetic or DIO mice and this improved when the mice were treated with AVE7688. IENF profiles were not decreased in diabetic or DIO NEP (-/-) mice. These studies suggest that NEP plays a role in regulating nerve function in insulin-deficient diabetes and DIO.
先前，我们已证实，通过使用血管肽酶抑制剂抑制中性内肽酶（NEP）——一种能降解血管活性肽和神经活性肽的蛋白酶，以及血管紧张素转换酶（ACE），可改善糖尿病大鼠模型的血管和神经功能。本研究旨在确定 NEP 和 ACE 的抑制或缺失是否可预防糖尿病或饮食诱导肥胖（DIO）引起的神经损伤。为了确定 NEP 和 ACE 抑制在与胰岛素缺乏性糖尿病或 DIO 相关的神经病变中的作用，我们使用 C57Bl/6J 小鼠进行了 AVE7688（一种血管肽酶抑制剂）处理，或使用 NEP 缺陷（-/-）小鼠。12 周龄的小鼠接受高脂肪饮食喂养 12 周，或在单次高剂量链脲佐菌素注射后 12 周内患有糖尿病。AVE7688 的治疗采用了预防和干预方案。DIO C57Bl/6J 和 NEP -/- 小鼠的葡萄糖利用率受损。然而，用 AVE7688 治疗 DIO C57Bl/6J 或 NEP -/- 小鼠可改善葡萄糖耐量。链脲佐菌素诱导的糖尿病和 DIO C57Bl/6J 小鼠均出现热痛觉减退和神经传导速度减慢，但在 AVE7688 治疗的 C57Bl/6J 小鼠或暴露于链脲佐菌素诱导的糖尿病或高脂肪饮食的 NEP -/- 小鼠中并未出现。C57Bl/6J 糖尿病或 DIO 小鼠的后足表皮内神经纤维（IENF）形态减少，用 AVE7688 治疗后有所改善。糖尿病或 DIO NEP（-/-）小鼠的 IENF 形态没有减少。这些研究表明，NEP 在调节胰岛素缺乏性糖尿病和 DIO 中的神经功能方面发挥作用。
