title: Cardiac glycosides provide neuroprotection against ischemic stroke: discovery by a brain slice-based compound screening platform.
abstract: We report here the results of a chemical genetic screen using small molecules with known pharmacologies coupled with a cortical brain slice-based model for ischemic stroke. We identified a small-molecule compound not previously appreciated to have neuroprotective action in ischemic stroke, the cardiac glycoside neriifolin, and demonstrated that its properties in the brain slice assay included delayed therapeutic potential exceeding 6 h. Neriifolin is structurally related to the digitalis class of cardiac glycosides, and its putative target is the Na(+)/K(+)-ATPase. Other cardiac glycoside compounds tested also showed neuroprotective activity, although with lower apparent potencies. In subsequent whole-animal studies, we found that neriifolin provided significant neuroprotection in a neonatal model of hypoxia/ischemia and in a middle cerebral artery occlusion model of transient focal ischemia. The neuroprotective potential of Na(+)/K(+)-ATPase is of particular interest because of its known "druggability"; indeed, Food and Drug Administration-approved, small-molecule compounds such as digitoxin and digoxin have been in clinical usage for congestive heart failure and arrhythmias for several decades. Thus, an existing cardiac glycoside or closely related compound could provide an accelerated path toward clinical trial testing for ischemic stroke. Our findings underscore the important role that hypothesis-neutral, high-content, tissue-based screens can play in the identification of new candidate drugs and drug targets for the treatment of diseases for which validated therapeutic pathways are not currently available.
authors.affiliation: *Cogent Neuroscience, Inc., Durham, NC 27704.
authors.forename: James K T
authors.initials: JKT
authors.lastname: Wang
authors.affiliation: *Cogent Neuroscience, Inc., Durham, NC 27704.
authors.forename: Stuart
authors.initials: S
authors.lastname: Portbury
authors.affiliation: *Cogent Neuroscience, Inc., Durham, NC 27704.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Thomas
authors.affiliation: *Cogent Neuroscience, Inc., Durham, NC 27704.
authors.forename: Shawn
authors.initials: S
authors.lastname: Barney
authors.affiliation: *Cogent Neuroscience, Inc., Durham, NC 27704.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Ricca
authors.affiliation: *Cogent Neuroscience, Inc., Durham, NC 27704.
authors.forename: Dexter L
authors.initials: DL
authors.lastname: Morris
authors.affiliation: Multidisciplinary Neuroprotection Laboratories and Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710; and.
authors.forename: David S
authors.initials: DS
authors.lastname: Warner
authors.affiliation: *Cogent Neuroscience, Inc., Durham, NC 27704; lo@neuro.duke.edu.|**Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, NC 27704.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Lo
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology* / Q000517:prevention & control*; D002298:Cardenolides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002301:Cardiac Glycosides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D066298:In Vitro Techniques; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002298:Cardenolides; D002301:Cardiac Glycosides; D018696:Neuroprotective Agents; C040684:neriifolin