PPBP [4-phenyl-1-(4-phenylbutyl) piperidine], a potent sigma-receptor ligand, decreases brain injury after transient focal ischemia in cats.
OBJECTIVE
We tested the hypothesis that administration of 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP), a potent sigma-receptor ligand, during transient focal ischemia would affect early postischemic brain injury.


METHODS
Halothane-anesthetized cats underwent left middle cerebral artery occlusion for 90 minutes followed by 4 hours of reperfusion. Control cats received saline (n = 10). Experimental cats (2 groups, n = 10 per group) were treated with PPBP at a rate of 0.1 mumol/kg per hour (PPBP-0.1) or administered 1 mumol/kg per hour (PPBP-1) intravenously from 75 minutes after initiation of ischemia and continuing during the 4 hours of reperfusion.


RESULTS
As measured by the microsphere method, blood flow to the ipsilateral caudate nucleus was decreased similarly in all groups during ischemia. Blood flow to the ipsilateral inferior temporal cortex was decreased during ischemia in all groups but was higher in cats subsequently treated with PPBP at the highest dose, even before drug administration. There was no difference in blood flow to the ipsilateral caudate nucleus or inferior temporal cortex (area of greatest cortical injury) during reperfusion. Triphenyltetrazolium-determined injury volume of the ipsilateral cerebral hemisphere (control, 29 +/- 5%; PPBP-0.1, 17 +/- 3%; PPBP-1, 6 +/- 1% of ipsilateral hemisphere; mean +/- SEM) and caudate nucleus (control, 49 +/- 5%; PPBP-0.1, 39 +/- 6%; PPBP-1, 25 +/- 5% of ipsilateral caudate nucleus) was less in cats treated with 1 mumol/kg per hour of PPBP compared with cats treated with saline. Cats treated with 0.1 mumol/kg per hour had a 45% smaller hemispheric injury volume than the control group without differences in intraischemic blood flow. Recovery of somatosensory evoked potential amplitude was greater in cats treated with PPBP-1 compared with control (control, 18 +/- 11%; PPBP-0.1, 30 +/- 14%; PPBP-1, 54 +/- 14% of baseline).


CONCLUSIONS
These data indicate that sigma-receptors may play an important role in the mechanism of acute injury in both the cortex and the caudate nucleus after 90 minutes of transient focal ischemia in the cat. Because PPBP afforded protection when administered at the end of ischemia and during reperfusion, sigma-receptors may contribute to the progression of injury in ischemic border regions.
Takahashi
H
H
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Md, USA.
Kirsch
J R
JR
Hashimoto
K
K
London
E D
ED
Koehler
R C
RC
Traystman
R J
RJ
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002415:Cats; D002421:Caudate Nucleus / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D002560:Cerebrovascular Circulation; D005073:Evoked Potentials, Somatosensory / Q000187:drug effects; D006220:Haloperidol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D007275:Injections, Intravenous; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000503:physiopathology*; D008024:Ligands; D018696:Neuroprotective Agents / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D010296:Parietal Lobe / Q000187:drug effects / Q000473:pathology; D017480:Receptors, sigma / Q000187:drug effects*; D015424:Reperfusion; D013194:Staining and Labeling; D013702:Temporal Lobe / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D013778:Tetrazolium Salts
D008024:Ligands; D018696:Neuroprotective Agents; D017480:Receptors, sigma; D013778:Tetrazolium Salts; C094850:4-phenyl-1-(4-phenylbutyl)piperidine; C009591:triphenyltetrazolium; D006220:Haloperidol