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Neuroprotection from focal ischemia by 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) is dependent on treatment duration in rats.

AbstractUNLABELLED:
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.
IMPLICATIONS:
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.
AuthorsI Harukuni, A Bhardwaj, R J Traystman, B Crain, E D London, J R Kirsch
JournalAnesthesia and analgesia (Anesth Analg) Vol. 87 Issue 6 Pg. 1299-305 (Dec 1998) ISSN: 0003-2999 [Print] United States
PMID9842816 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Neuroprotective Agents
  • 4-phenyl-1-(4-phenylbutyl)piperidine
  • Haloperidol
Topics
  • Animals
  • Brain Ischemia (pathology, physiopathology, prevention & control)
  • Cerebral Infarction (pathology)
  • Haloperidol (administration & dosage, analogs & derivatives, pharmacology)
  • Infusions, Intravenous
  • Male
  • Neuroprotective Agents (administration & dosage, pharmacology)
  • Rats
  • Rats, Wistar
  • Reperfusion
  • Time Factors

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