sigma(1)-receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine affords neuroprotection from focal ischemia with prolonged reperfusion

Background and Purpose-We previously showed that the intravenous administra tion of the potent sigma(1)-receptor ligand 4-phenyl-1-(4-phenylbutyl)-pipe ridine (PPBP) provides neuroprotection against transient focal cerebral isc hemia 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 neurob ehavioral outcome and infarction volume. Methods-Under the controlled conditions of normoxia, normocarbia, and normo thermia, halothane-anesthetized male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAO) with the intraluminal suture occ lusion technique. We used laser Doppler flowmetry to assess MCAO, At 60 min utes after the onset of ischemia, rats were randomly assigned to 1 of 4 tre atment groups in a blinded fashion and received a continuous intravenous in fusion of control saline or 0.1, 1, or 10 mu mol . 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 ass essed with triphenyltetrazolium chloride staining on day 7 of reperfusion i n all rats. Results-Triphenyltetrazolium chloride-determined infarction volume of ipsil ateral cortex was smaller in rats treated with 10 mu mol . kg(-1) . h(-1) P PBP (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+/-1 1 mm(3), 31+/-3% of contralateral structure). PPBP did not provide signific ant neuroprotection in the caudoputamen complex. Although MCAO was associat ed with several alterations in behavior, the treatment with PPBP had no eff ect on behavioral outcomes. Conclusions-The data demonstrate that the potent sigma(1)-receptor ligand P PBP decreases cortical infarction volume without altering neurobehavior aft er transient focal ischemia and prolonged reperfusion in the rat.