title: Neuroprotection from focal ischemia by 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) is dependent on treatment duration in rats.
abstract: The IV administration of the potent sigma1-receptor ligand 4-phenyl-1-(4-phenylbutyl)piperidine (PPBP) provides neuroprotection against focal cerebral ischemia. We tested the hypothesis that prolonged, continuous administration of PPBP would provide further neuroprotection in a rat model of transient focal ischemia and reperfusion. Under controlled conditions of normoxia, normocarbia, and normothermia, halothane-anesthetized male Wistar rats were subjected to 2 h of middle cerebral artery occlusion by the intraluminal occlusion technique. Sixty minutes after the onset of ischemia, rats were randomly assigned to six treatment groups to receive a continuous IV infusion of PPBP (1 micromol . kg(-1). h(-1) for 1, 2, 3, or 4 days or saline for 1 or 4 days. The infarction volume was assessed by triphenyltetrazolium chloride (TFC) staining on Day 4 after ischemia in all rats. The TTC-determined infarction volume of the ipsilateral cerebral cortex was smaller in rats treated with PPBP for 1 day (42+/-13 mm3; 10%+/-3% of ipsilateral hemisphere; P < 0.05) (mean+/-SEM) compared with that in corresponding 1-day control rats (124+/-22 mm; 29%+/-5% of ipsilateral hemisphere; P < 0.05) or 4-day control rats (112+/-10 mm; 26%+/-2% of ipsilateral hemisphere; P < 0.05). Cortical infarction volumes in 2-, 3-, and 4-day PPBP-treated rats were not different compared with 1- and 4-day saline-treated controls. These data demonstrate that the sigma1(-receptor ligand PPBP attenuates ischemic injury when administration is initiated 60 min after the onset of focal ischemia but that prolonged continuous treatment with PPBP beyond 24 h provides no neuroprotection.
  
  
  CONCLUSIONS
  sigma-Ligands decrease infarction size in various animal models when given after the onset of stroke. Prolonged treatment with a potent sigma-ligand is associated with loss of therapeutic efficacy for this compound.
authors.affiliation: Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: I
authors.initials: I
authors.lastname: Harukuni
authors.forename: A
authors.initials: A
authors.lastname: Bhardwaj
authors.forename: R J
authors.initials: RJ
authors.lastname: Traystman
authors.forename: B
authors.initials: B
authors.lastname: Crain
authors.forename: E D
authors.initials: ED
authors.lastname: London
authors.forename: J R
authors.initials: JR
authors.lastname: Kirsch
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002544:Cerebral Infarction / Q000473:pathology; D006220:Haloperidol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D007262:Infusions, Intravenous; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015424:Reperfusion; D013997:Time Factors
chemical_list: D018696:Neuroprotective Agents; C094850:4-phenyl-1-(4-phenylbutyl)piperidine; D006220:Haloperidol