title: A translational paradigm for the preclinical evaluation of the stroke neuroprotectant Tat-NR2B9c in gyrencephalic nonhuman primates.
abstract: Over decades, all attempts to translate acute stroke neuroprotectants from discovery in lower-order species to human clinical use have failed. This raised concerns about the predictive validity of preclinical studies in animals for outcomes in human stroke trials. To bridge this translational gap, we used high-order gyrencephalic nonhuman primates subjected to an experimental protocol that mimicked that of a corresponding, separately reported, clinical trial in which the human subjects underwent endovascular cerebral aneurysm repair. Both placebo-controlled studies tested neuroprotection by Tat-NR2B9c, a prospective therapeutic compound, in anesthetized subjects. Embolic strokes were produced by small intra-arterial emboli caused by the endovascular procedure. We show that primates treated with Tat-NR2B9c after the onset of embolic strokes exhibited significantly reduced numbers and volumes of strokes, as visualized by diffusion- and T2-weighted magnetic resonance imaging. These results correctly anticipated the outcome of the corresponding human trial, thus validating this study design as a predictor of neuroprotective efficacy in humans. This strategy may facilitate the evaluation of promising neuroprotectants before undertaking similar studies in human subjects.
authors.affiliation: Toronto Western Hospital Research Institute, Department of Physiology, University of Toronto, Toronto, Ontario M5T 2S8, Canada.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Cook
authors.forename: Lucy
authors.initials: L
authors.lastname: Teves
authors.forename: Michael
authors.initials: M
authors.lastname: Tymianski
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D008279:Magnetic Resonance Imaging; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010455:Peptides / Q000627:therapeutic use*; D011323:Primates; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology
chemical_list: D018696:Neuroprotective Agents; D010455:Peptides; C542597:Tat-NR2B9c