Antonic, A and Dottori, M and Macleod, MR and Donnan, GA and Howells, DW, NXY-059, a failed stroke neuroprotectant, offers no protection to stem cell-derived human neurons, Journal of Stroke and Cerebrovascular Diseases, 27, (8) pp. 2158-2165. ISSN 1052-3057 (2018) [Refereed Article]
Copyright 2018 National Stroke Association
Background: 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.
Materials and Methods: 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.
Results: 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 Ám to 1 mm was completely without activity. Conversely an antioxidant cocktail comprising 100 Ám each of ascorbate, reduced glutathione, and dithiothreitol used as a positive control provided marked neuronal protection in these assays.
Conclusion: 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.
|Item Type:||Refereed Article|
|Keywords:||neuroprotection, ischemic stroke, stem cells, NXY-059|
|Research Division:||Biomedical and Clinical Sciences|
|Research Group:||Cardiovascular medicine and haematology|
|Research Field:||Cardiology (incl. cardiovascular diseases)|
|Objective Group:||Clinical health|
|Objective Field:||Clinical health not elsewhere classified|
|UTAS Author:||Howells, DW (Professor David Howells)|
|Web of Science® Times Cited:||11|
Repository Staff Only: item control page