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.