title: Identification of isoxsuprine hydrochloride as a neuroprotectant in ischemic stroke through cell-based high-throughput screening.
abstract: Stroke is a leading cause of death and disability and treatment options are limited. A promising approach to accelerate the development of new therapeutics is the use of high-throughput screening of chemical libraries. Using a cell-based high-throughput oxygen-glucose deprivation (OGD) model, we evaluated 1,200 small molecules for repurposed application in stroke therapy. Isoxsuprine hydrochloride was identified as a potent neuroprotective compound in primary neurons exposed to OGD. Isoxsuprine, a β2-adrenergic agonist and NR2B subtype-selective N-methyl-D-aspartate (NMDA) receptor antagonist, demonstrated no loss of efficacy when administered up to an hour after reoxygenation in an in vitro stroke model. In an animal model of transient focal ischemia, isoxsuprine significantly reduced infarct volume compared to vehicle (137 ± 18 mm3 versus 279 ± 25 mm3, p < 0.001). Isoxsuprine, a peripheral vasodilator, was FDA approved for the treatment of cerebrovascular insufficiency and peripheral vascular disease. Our demonstration of the significant and novel neuroprotective action of isoxsuprine hydrochloride in an in vivo stroke model and its history of human use suggest that isoxsuprine may be an ideal candidate for further investigation as a potential stroke therapeutic.
authors.affiliation: University of New Mexico Health Sciences Center, Department of Neurology, Albuquerque, New Mexico, United States of America.
authors.forename: Jeff W
authors.initials: JW
authors.lastname: Hill
authors.affiliation: University of New Mexico Health Sciences Center, Department of Neurology, Albuquerque, New Mexico, United States of America.
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Thompson
authors.affiliation: Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Carter
authors.affiliation: Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Edwards
authors.affiliation: Center for Molecular Discovery, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, United States of America.
authors.forename: Larry A
authors.initials: LA
authors.lastname: Sklar
authors.affiliation: University of New Mexico Health Sciences Center, Department of Neurology, Albuquerque, New Mexico, United States of America.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Rosenberg
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D004195:Disease Models, Animal; D007556:Isoxsuprine / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy*
chemical_list: D018696:Neuroprotective Agents; D007556:Isoxsuprine