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

The IV administration of the potent σ₁-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 μmol · 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 (TTC) 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 σ₁-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: σ-Ligands decrease infarction size in various animal models when given after the onset of stroke. Prolonged treatment with a potent σ-ligand is associated with loss of therapeutic efficacy for this compound.