title: A prototypical Sigma-1 receptor antagonist protects against brain ischemia.
abstract: Previous studies indicate that the Sigma-1 ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) protects the brain from ischemia. Less clear is whether protection is mediated by agonism or antagonism of the Sigma-1 receptor, and whether drugs already in use for other indications and that interact with the Sigma-1 receptor might also prevent oxidative damage due to conditions such as cerebral ischemic stroke. The antipsychotic drug haloperidol is an antagonist of Sigma-1 receptors and in this study it potently protects against oxidative stress-related cell death in vitro at low concentrations. The protective potency of haloperidol and a number of other butyrophenone compounds positively correlate with their affinity for a cloned Sigma-1 receptor, and the protection is mimicked by a Sigma-1 receptor-selective antagonist (BD1063), but not an agonist (PRE-084). In vivo, an acute low dose (0.05 mg/kg s.c.) of haloperidol reduces by half the ischemic lesion volume induced by a transient middle cerebral artery occlusion. These in vitro and in vivo pre-clinical results suggest that a low dose of acutely administered haloperidol might have a novel application as a protective agent against ischemic cerebral stroke and other types of brain injury with an ischemic component.
authors.affiliation: Department of Pharmacology and Neuroscience, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107-2699, USA. jschetz@hsc.unt.edu
authors.forename: John A
authors.initials: JA
authors.lastname: Schetz
authors.forename: Evelyn
authors.initials: E
authors.lastname: Perez
authors.forename: Ran
authors.initials: R
authors.lastname: Liu
authors.forename: Shiuhwei
authors.initials: S
authors.lastname: Chen
authors.forename: Ivan
authors.initials: I
authors.lastname: Lee
authors.forename: James W
authors.initials: JW
authors.lastname: Simpkins
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006220:Haloperidol / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D000097605:Sigma-1 Receptor
chemical_list: D006220:Haloperidol; D018696:Neuroprotective Agents; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor