Emery S M, Dobrowsky R T
The University of Kansas, Lawrence, KS, United States.
The University of Kansas, Lawrence, KS, United States.
Int Rev Neurobiol. 2016;127:181-210. doi: 10.1016/bs.irn.2016.03.001. Epub 2016 Apr 5.
The etiology of diabetic peripheral neuropathy (DPN) involves an interrelated series of metabolic and vascular insults that ultimately contribute to sensory neuron degeneration. In the quest to pharmacologically manage DPN, small-molecule inhibitors have targeted proteins and pathways regarded as "diabetes specific" as well as others whose activity are altered in numerous disease states. These efforts have not yielded any significant therapies, due in part to the complicating issue that the biochemical contribution of these targets/pathways to the progression of DPN does not occur with temporal and/or biochemical uniformity between individuals. In a complex, chronic neurodegenerative disease such as DPN, it is increasingly appreciated that effective disease management may not necessarily require targeting a pathway or protein considered to contribute to disease progression. Alternatively, it may prove sufficiently beneficial to pharmacologically enhance the activity of endogenous cytoprotective pathways to aid neuronal tolerance to and recovery from glucotoxic stress. In pursuing this paradigm shift, we have shown that modulating the activity and expression of molecular chaperones such as heat shock protein 70 (Hsp70) may provide translational potential for the effective medical management of insensate DPN. Considerable evidence supports that modulating Hsp70 has beneficial effects in improving inflammation, oxidative stress, and glucose sensitivity. Given the emerging potential of modulating Hsp70 to manage DPN, the current review discusses efforts to characterize the cytoprotective effects of this protein and the benefits and limitations that may arise in drug development efforts that exploit its cytoprotective activity.
糖尿病周围神经病变(DPN)的病因涉及一系列相互关联的代谢和血管损伤,最终导致感觉神经元变性。在寻求药物治疗DPN的过程中,小分子抑制剂靶向了被认为是“糖尿病特异性”的蛋白质和信号通路,以及其他在多种疾病状态下活性发生改变的蛋白质和信号通路。这些努力尚未产生任何显著的治疗方法,部分原因是一个复杂的问题,即这些靶点/信号通路对DPN进展的生化贡献在个体之间不存在时间和/或生化一致性。在诸如DPN这样的复杂慢性神经退行性疾病中,人们越来越认识到,有效的疾病管理不一定需要靶向被认为是导致疾病进展的信号通路或蛋白质。相反,药理增强内源性细胞保护信号通路的活性以帮助神经元耐受糖毒性应激并从中恢复,可能被证明具有足够的益处。在追求这种范式转变的过程中,我们已经表明,调节分子伴侣如热休克蛋白70(Hsp70)的活性和表达,可能为感觉减退型DPN的有效药物管理提供转化潜力。大量证据支持调节Hsp70在改善炎症、氧化应激和葡萄糖敏感性方面具有有益作用。鉴于调节Hsp70治疗DPN的潜在新进展,本综述讨论了表征该蛋白细胞保护作用的研究工作,以及在利用其细胞保护活性的药物开发工作中可能出现的益处和局限性。