Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia.
Handb Exp Pharmacol. 2021;264:395-423. doi: 10.1007/164_2020_391.
A range of chemically different compounds are known to inhibit the formation and accumulation of advanced glycation end products (AGEs) or disrupt associated signalling pathways. There is evidence that some of these agents can provide end-organ protection in chronic diseases including diabetes. Whilst this group of therapeutics are structurally and functionally different and have a range of mechanisms of action, they ultimately reduce the deleterious actions and the tissue burden of advanced glycation end products. To date it remains unclear if this is due to the reduction in tissue AGE levels per se or the modulation of downstream signal pathways. Some of these agents either stimulate antioxidant defence or reduce the formation of reactive oxygen species (ROS), modify lipid profiles and inhibit inflammation. A number of existing treatments for glucose lowering, hypertension and hyperlipidaemia are also known to reduce AGE formation as a by-product of their action. Targeted AGE formation inhibitors or AGE cross-link breakers have been developed and have shown beneficial effects in animal models of diabetic complications as well as other chronic conditions. However, only a few of these agents have progressed to clinical development. The failure of clinical translation highlights the importance of further investigation of the advanced glycation pathway, the diverse actions of agents which interfere with AGE formation, cross-linking or AGE receptor activation and their effect on the development and progression of chronic diseases including diabetic complications. Advanced glycation end products (AGEs) are (1) proteins or lipids that become glycated as a result of exposure to sugars or (2) non-proteinaceous oxidised lipids. They are implicated in ageing and the development, or worsening, of many degenerative diseases, such as diabetes, atherosclerosis, chronic kidney and Alzheimer's disease. Several antihypertensive and antidiabetic agents and statins also indirectly lower AGEs. Direct AGE inhibitors currently investigated include pyridoxamine and epalrestat, the inhibition of the formation of reactive dicarbonyls such as methylglyoxal as an important precursor of AGEs via increased activation of the detoxifying enzyme Glo-1 and inhibitors of NOX-derived ROS to reduce the AGE/RAGE signalling.
已知一系列化学性质不同的化合物能够抑制晚期糖基化终末产物（AGEs）的形成和积累，或破坏相关信号通路。有证据表明，这些药物中的一些可以在包括糖尿病在内的慢性疾病中提供靶器官保护。虽然这组治疗药物在结构和功能上有所不同，且具有多种作用机制，但它们最终都减少了晚期糖基化终末产物的有害作用和组织负担。迄今为止，尚不清楚这是由于组织 AGE 水平本身的降低还是下游信号通路的调节所致。其中一些药物可以刺激抗氧化防御或减少活性氧（ROS）的形成，改变脂质谱并抑制炎症。一些现有的降低葡萄糖、高血压和高血脂的治疗方法也已知会减少 AGE 形成，这是其作用的副产品。已经开发出了靶向 AGE 形成抑制剂或 AGE 交联破坏剂，并在糖尿病并发症的动物模型以及其他慢性疾病中显示出有益效果。然而，只有少数这些药物已经进入临床开发阶段。临床转化的失败凸显了进一步研究晚期糖基化途径、干扰 AGE 形成、交联或 AGE 受体激活的药物的多样性作用以及它们对包括糖尿病并发症在内的慢性疾病的发展和进展的重要性。晚期糖基化终末产物（AGEs）是（1）由于暴露于糖而糖化的蛋白质或脂质，或（2）非蛋白质氧化脂质。它们与衰老以及许多退行性疾病的发生或恶化有关，如糖尿病、动脉粥样硬化、慢性肾病和阿尔茨海默病。几种降压药和降糖药以及他汀类药物也间接降低 AGEs。目前正在研究的直接 AGE 抑制剂包括吡哆胺和依帕司他，通过增加解毒酶 Glo-1 的激活，抑制形成重要 AGE 前体的活性二羰基化合物（如甲基乙二醛），以及抑制 NOX 衍生的 ROS 来减少 AGE/RAGE 信号，从而抑制 AGE 的形成。
