Cameron Norman E, Gibson T Michael, Nangle Matthew R, Cotter Mary A
School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK.
Ann N Y Acad Sci. 2005 Jun;1043:784-92. doi: 10.1196/annals.1333.091.
Advanced glycation and lipoxidation end products (AGEs/ALEs) have been implicated in the pathogenesis of the major microvascular complications of diabetes mellitus: nephropathy, neuropathy, and retinopathy. This article reviews the evidence regarding the peripheral nerve and its vascular supply. Most investigations done to assess the role of AGEs/ALEs in animal models of diabetic neuropathy have used aminoguanidine as a prototypic inhibitor. Preventive or intervention experiments have shown treatment benefits for motor and sensory nerve conduction velocity, autonomic nitrergic neurotransmission, nerve morphometry, and nerve blood flow. The latter depends on improvements in nitric oxide-mediated endothelium-dependent vasodilation and is responsible for conduction velocity improvements. A mechanistic interpretation of aminoguanidine's action in terms of AGE/ALE inhibition is made problematic by the relative lack of specificity. However, other unrelated compounds, such as pyridoxamine and pyridoxamine analogues, have recently been shown to have beneficial effects similar to aminoguanidine, as well as to improve pain-related measures of thermal hyperalgesia and tactile allodynia. These data also stress the importance of redox metal ion-catalyzed AGE/ALE formation. A further approach is to decrease substrate availability by reducing the elevated levels of hexose and triose phosphates found in diabetes. Benfotiamine is a transketolase activator that directs these substrates to the pentose phosphate pathway, thus reducing tissue AGEs. A similar spectrum of improvements in nerve and vascular function were noted when using benfotiamine in diabetic rats. Taken together, the data provide strong support for an important role for AGEs/ALEs in the etiology of diabetic neuropathy.
晚期糖基化终末产物和晚期脂质氧化终产物（AGEs/ALEs）与糖尿病主要微血管并发症（肾病、神经病变和视网膜病变）的发病机制有关。本文综述了有关周围神经及其血管供应的证据。大多数评估AGEs/ALEs在糖尿病性神经病变动物模型中作用的研究都使用氨基胍作为典型抑制剂。预防性或干预性实验已表明，对运动和感觉神经传导速度、自主神经一氧化氮能神经传递、神经形态测定和神经血流有治疗益处。后者取决于一氧化氮介导的内皮依赖性血管舒张的改善，并负责传导速度的提高。由于相对缺乏特异性，氨基胍作用的机制性解释在AGE/ALE抑制方面存在问题。然而，最近已表明，其他不相关的化合物，如吡哆胺及其类似物，具有与氨基胍相似的有益作用，还能改善与疼痛相关的热痛觉过敏和触觉异常性疼痛指标。这些数据也强调了氧化还原金属离子催化的AGE/ALE形成的重要性。另一种方法是通过降低糖尿病中发现的己糖和磷酸丙糖升高水平来减少底物可用性。苯磷硫胺是一种转酮醇酶激活剂，可将这些底物导向磷酸戊糖途径，从而减少组织AGEs。在糖尿病大鼠中使用苯磷硫胺时，也观察到了类似的神经和血管功能改善情况。综上所述，这些数据为AGEs/ALEs在糖尿病性神经病变病因中起重要作用提供了有力支持。
