A prototypical Sigma-1 receptor antagonist protects against brain ischemia

John A. Schetz, Evelyn Perez, Ran Liu, Shiuhwei Chen, Ivan Lee, James W. Simpkins

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


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.

Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalBrain Research
Issue number1
StatePublished - 21 Nov 2007


  • Acute stroke treatment
  • Antipsychotic
  • Cerebral ischemic stroke
  • Neuroleptic
  • Neuroprotection
  • Oxidative stress
  • Sigma receptor


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