Antonic Ana, Dottori Mirella, Macleod Malcolm R, Donnan Geoffrey A, Howells David W
Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, Heidelberg, Victoria, Australia; Department of Neuroscience, Central Clinical School, Monash University, The Alfred Centre, Victoria, Australia.
Illawarra Health and Medical Research Institute, Centre for Molecular and Medical Bioscience, University of Wollongong, Wollongong, New South Wales, Australia.
J Stroke Cerebrovasc Dis. 2018 Aug;27(8):2158-2165. doi: 10.1016/j.jstrokecerebrovasdis.2018.03.015. Epub 2018 Apr 16.
Developing new medicines is a complex process where understanding the reasons for both failure and success takes us forward. One gap in our understanding of most candidate stroke drugs before clinical trial is whether they have a protective effect on human tissues. NXY-059 is a spin-trap reagent hypothesized to have activity against the damaging oxidative biology which accompanies ischemic stroke. Re-examination of the preclinical in vivo dataset for this agent in the wake of the failed SAINT-II RCT highlighted the presence of a range of biases leading to overestimation of the magnitude of NXY-059's effects in laboratory animals. Therefore, NXY-059 seemed an ideal candidate to evaluate in human neural tissues to determine whether human tissue testing might improve screening efficiency.
The aim of this randomized and blinded study was to assess the effects of NXY-059 on human stem cell-derived neurons in the presence of ischemia-like injury induced by oxygen glucose deprivation or oxidative stress induced by hydrogen peroxide or sodium nitroprusside.
In MTT assays of cell survival, lactate dehydrogenase assays of total cell death and terminal deoxynucleotidyl transferase dUTP nick end labeling staining of apoptotic-like cell death, NXY-059 at concentrations ranging from 1 µm to 1 mm was completely without activity. Conversely an antioxidant cocktail comprising 100 µm each of ascorbate, reduced glutathione, and dithiothreitol used as a positive control provided marked neuronal protection in these assays.
These findings support our hypothesis that stroke drug screening in human neural tissues will be of value and provides an explanation for the failure of NXY-059 as a human stroke drug.
开发新药是一个复杂的过程，了解失败和成功的原因能推动我们前进。在临床试验之前，我们对大多数候选中风药物的理解存在一个差距，即它们是否对人体组织有保护作用。NXY - 059是一种自旋捕捉试剂，据推测它对伴随缺血性中风的有害氧化生物学具有活性。在SAINT - II随机对照试验失败后，对该药物的临床前体内数据集进行重新审查时发现存在一系列偏差，导致在实验动物中高估了NXY - 059的作用程度。因此，NXY - 059似乎是评估人体神经组织的理想候选药物，以确定人体组织测试是否可以提高筛选效率。
这项随机双盲研究的目的是评估NXY - 059在氧糖剥夺诱导的缺血样损伤或过氧化氢或硝普钠诱导的氧化应激存在的情况下对人干细胞衍生神经元的影响。
在细胞存活的MTT测定、总细胞死亡的乳酸脱氢酶测定以及凋亡样细胞死亡的末端脱氧核苷酸转移酶dUTP缺口末端标记染色中，浓度范围为1μm至1mm的NXY - 059完全没有活性。相反，作为阳性对照的包含100μm抗坏血酸、还原型谷胱甘肽和二硫苏糖醇的抗氧化剂混合物在这些测定中提供了显著的神经元保护作用。
这些发现支持了我们的假设，即人体神经组织中的中风药物筛选将具有价值，并为NXY - 059作为人类中风药物的失败提供了解释。
Zotero 插件