title: Efficacy of the PSD95 inhibitor Tat-NR2B9c in mice requires dose translation between species.
abstract: Tat-NR2B9c, a clinical-stage stroke neuroprotectant validated in rats and primates, was recently deemed ineffective in mice. To evaluate this discrepancy, we conducted studies in mice subjected to temporary middle cerebral artery occlusion (tMCAO) for either 30 or 60 min according to the established principles for dose-translation between species. Tat-NR2B9c treatment reduced infarct volume by by 24.5% (p = 0.49) and 26.0% (p = 0.03) for 30 and 60 min tMCAO, respectively, at the rat-equivalent dose of 10 nMole/g, but not at the previously reported 3 nMole/g in mice. Dose translation is thus critical when preclinical experiments are conducted in new species.
authors.affiliation: Toronto Western Hospital Research Institute, Toronto, Ontario, Canada.
authors.forename: Lucy M
authors.initials: LM
authors.lastname: Teves
authors.affiliation: Toronto Western Hospital Research Institute, Toronto, Ontario, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Cui
authors.affiliation: Toronto Western Hospital Research Institute, Toronto, Ontario, Canada Department of Physiology, University of Toronto, Toronto, Ontario, Canada Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada Department of Surgery, University of Toronto, Toronto, Ontario, Canada mike.tymianski@uhn.ca.
authors.forename: Michael
authors.initials: M
authors.lastname: Tymianski
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D013045:Species Specificity
chemical_list: D018696:Neuroprotective Agents; D010455:Peptides; C542597:Tat-NR2B9c
keywords: Neuroprotection; animal models; excitotoxicity; focal ischemia; synapses/dendrites