sigma(1)-receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine affords neuroprotection from focal ischemia with prolonged reperfusion.
OBJECTIVE
We previously showed that the intravenous administration of the potent final sigma(1)-receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine (PPBP) provides neuroprotection against transient focal cerebral ischemia and that the protection depends on treatment duration. We tested the hypothesis that PPBP would provide neuroprotection in a model of transient focal ischemia and 7 days of reperfusion in the rat as assessed with neurobehavioral outcome and infarction volume.


METHODS
Under the controlled conditions of normoxia, normocarbia, and normothermia, halothane-anesthetized male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAO) with the intraluminal suture occlusion technique. We used laser Doppler flowmetry to assess MCAO. At 60 minutes after the onset of ischemia, rats were randomly assigned to 1 of 4 treatment groups in a blinded fashion and received a continuous intravenous infusion of control saline or 0.1, 1, or 10 micromol. kg(-1). h(-1) PPBP for 24 hours. Neurobehavioral evaluation was performed at baseline (3 to 4 days before MCAO) and at 3 and 7 days of reperfusion. Infarction volume was assessed with triphenyltetrazolium chloride staining on day 7 of reperfusion in all rats.


RESULTS
Triphenyltetrazolium chloride-determined infarction volume of ipsilateral cortex was smaller in rats treated with 10 micromol. kg(-1). h(-1) PPBP (n=15, 68+/-12 mm(3), 18+/-3% of contralateral structure, P<0.05) (mean+/-SEM) compared with corresponding rats treated with saline (n=15, 114+/-11 mm(3), 31+/-3% of contralateral structure). PPBP did not provide significant neuroprotection in the caudoputamen complex. Although MCAO was associated with several alterations in behavior, the treatment with PPBP had no effect on behavioral outcomes.


CONCLUSIONS
The data demonstrate that the potent final sigma(1)-receptor ligand PPBP decreases cortical infarction volume without altering neurobehavior after transient focal ischemia and prolonged reperfusion in the rat.
Harukuni
I
I
Departments of Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287-4963, USA.
Bhardwaj
A
A
Shaivitz
A B
AB
DeVries
A C
AC
London
E D
ED
Hurn
P D
PD
Traystman
R J
RJ
Kirsch
J R
JR
Faraci
F M
FM
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology*; D004334:Drug Administration Schedule; D006220:Haloperidol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D008024:Ligands; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000378:metabolism*; D015427:Reperfusion Injury / Q000473:pathology*
D008024:Ligands; D018696:Neuroprotective Agents; D017480:Receptors, sigma; C094850:4-phenyl-1-(4-phenylbutyl)piperidine; D006220:Haloperidol