σ₁-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 administration of the potent σ₁-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 μmol · 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 μmol · kg^-1 · h^-1 PPBP (n=15, 68±12 mm³, 18±3% of contralateral structure, P<0.05) (mean±SEM) compared with corresponding rats treated with saline (n= 15, 114±11 mm³, 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 σ₁-receptor ligand PPBP decreases cortical infarction volume without altering neurobehavior after transient focal ischemia and prolonged reperfusion in the rat.