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首页> 外文期刊>Free Radical Biology and Medicine: The Official Journal of the Oxygen Society >Poly(ADP-ribose) polymerase inhibition as a novel therapeutic approach against intraepidermal nerve fiber loss and neuropathic pain associated with advanced diabetic neuropathy: a commentary on 'PARP Inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy'.
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Poly(ADP-ribose) polymerase inhibition as a novel therapeutic approach against intraepidermal nerve fiber loss and neuropathic pain associated with advanced diabetic neuropathy: a commentary on 'PARP Inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy'.

机译：聚（ADP-核糖）聚合酶抑制是一种针对表皮内神经纤维丢失和与晚期糖尿病性神经病相关的神经性疼痛的新型治疗方法：评述“ PARP抑制或基因缺陷可抵消晚期糖尿病性神经病中的表皮内神经纤维丧失和神经性疼痛”。

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Diabetes mellitus is the most common cause of neuropathy which is estimated to affect 20-30 million people worldwide . Clinical trials in subjects with Type 1 and Type 2 diabetes indicate that intensive therapy and improved blood glucose control reduce the incidence and slow progression of diabetic neuropathy, thus implicating hyperglycemia as a leading causative factor . Numerous mechanisms have been proposed to link chronic hyperglycemia to diabetic cardiovascular complications, nephropathy, and impairments in motor and sensory nerve functions among other manifestations of peripheral diabetic neuropathy (PDN, reviewed in [2-4]). It has been hypothesized that hyperglycemia-induced overproduction of superoxide by the mitochondrial electron-transport chain activates multiple pathways of cell injury (e.g., protein kinase C (PKC), advanced glycosylation end product formation (AGE), hexosamine and polyol pathway fluxes, and nuclear factor-KB signaling, among many others) by inhibiting glyceraIdehyde-3-phosphate dehydrogenase (GAPDH) activity in endothelial cells . The hyperglyce-mia-induced enhanced mitochondrial superoxide and iNOS-derived nitric oxide (NO) formation favor the generation of reactive oxidant peroxynitrite through diffusion-controlled reaction in the vascular endothelium and smooth muscle . Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms, triggering cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury , Oxidative DNA damage also leads to the overactivation of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP; the most abundant isoform of the PARP enzyme family), which depletes its substrate NAD(+), slowing the rate of glycolysis, electron transport, and ATP formation on one hand . On the other hand, it inhibits GAPDH by poly(ADP-ribosyl)ation and may also be involved in the regulation of various important inflammatory pathways . These processes.lead to acute endothelial dysfunction in diabetic vessels both in experimental animals [6-10] and in humans [11], a concept pioneered by Dr. Szabo's group (reviewed in ). According to the vascular concept of diabetic neuropathy [12], endothelial dysfunction in vasa nervorum (small vessels supplying nerves) results in a decrease in nerve blood flow and endoneurial hypoxia, eventually culminating into functional and morphological changes in the diabetic nerves. The neurochemical concept of PDN suggests the importance of similar mechanisms in the neural elements (e.g., Schwann cells and neurons).
机译：糖尿病是神经病的最常见原因，据估计影响全世界20-30百万人。在1型和2型糖尿病患者中进行的临床试验表明，强化治疗和改善的血糖控制可降低糖尿病性神经病的发生率和进展缓慢，因此暗示高血糖是主要的病因。已经提出了许多机制来将慢性高血糖与糖尿病性心血管并发症，肾病，运动神经和感觉神经功能受损以及周围性糖尿病神经病变的其他表现联系起来（PDN，在[2-4]中进行了综述）。假设线粒体电子传输链由高血糖症引起的超氧化物过度生产激活了细胞损伤的多种途径（例如蛋白激酶C（PKC），晚期糖基化终产物形成（AGE），六胺和多元醇途径通量，以及核因子-κB信号转导等），通过抑制内皮细胞中的3-磷酸甘油醛脱氢酶（GAPDH）活性来实现。高血糖症引起的线粒体超氧化物增强和iNOS衍生的一氧化氮（NO）的形成有利于通过血管内皮和平滑肌中的扩散控制反应生成反应性氧化剂过氧亚硝酸盐。过氧亚硝酸盐通过直接的氧化反应或通过间接的自由基介导的机制与脂质，DNA和蛋白质相互作用，从而触发细胞反应，范围从细胞信号的微妙调节到压倒性的氧化损伤，氧化性DNA损伤也导致核酶多聚酶的过度活化。 （ADP-核糖）聚合酶-1（PARP; PARP酶家族中最丰富的同工型），一方面耗尽了其底物NAD（+），一方面减慢了糖酵解，电子转运和ATP形成的速度。另一方面，它通过聚（ADP-核糖基）化抑制GAPDH，并且还可能参与各种重要炎症途径的调节。这些过程导致实验动物[6-10]和人类[11]的糖尿病血管中急性内皮功能障碍，这是Szabo博士的研究小组率先提出的概念（在中进行了综述）。根据糖尿病性神经病变的血管概念[12]，神经脉管（供应神经的小血管）中的内皮功能障碍导致神经血流量减少和神经内膜缺氧，最终导致糖尿病神经功能和形态的改变。 PDN的神经化学概念表明，神经元（例如雪旺细胞和神经元）中类似机制的重要性。

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