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(Stroke. 1996;27:2120-2123.)
© 1996 American Heart Association, Inc.

Articles

PPBP [4-Phenyl-1-(4-phenylbutyl) Piperidine] Decreases Brain Injury After Transient Focal Ischemia in Rats

Hiroshi Takahashi, MD; Jeffrey R. Kirsch, MD; Kenji Hashimoto, PhD; Edythe D. London, PhD; Raymond C. Koehler, PhD Richard J. Traystman, PhD

the Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions (H.T., J.R.K., R.C.K., R.J.T.), and the Neuroimaging and Drug Action Section, Division of Intramural Research, National Institute on Drug Abuse (K.H., E.D.L.), Baltimore, Md.

	Abstract

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Background and Purpose We tested the hypothesis that intravenous administration of the potent -receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) during transient focal ischemia would decrease postischemic brain infarction volume in rats.

Methods Rats underwent intravascular focal ischemia for 2 hours followed by 22 hours of reperfusion. Halothane anesthesia was used only during initiation and cessation of ischemia. Rats received saline (n=10) or 1 µmol/kg per hour PPBP (n=10) by continuous intravenous infusion starting 1 hour after the initiation of ischemia and continuing through 22 hours of reperfusion.

Results There was no difference between groups in blood pressure, arterial blood gas values, and body temperature. Triphenyltetrazolium-determined infarction volume of ipsilateral cerebral cortex (saline, 39±6%; PPBP, 21±7% of ipsilateral hemisphere; mean±SEM) and striatum (saline, 68±6%; PPBP, 33±8% of ipsilateral striatum) was smaller in rats treated with PPBP than in rats treated with saline.

Conclusions These data indicate that -receptors may play an important role in the mechanism of injury both in cortex and striatum after 2 hours of transient focal ischemia in rats. Because PPBP afforded protection when administered at the end of ischemia and during reperfusion, -receptors may influence the progression of injury in ischemic border regions.

Key Words: cerebral ischemia, focal • neuronal damage • receptors, sigma • rats

	Introduction

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Because -receptor ligands modulate the neuronal response to pharmacological stimulation of the NMDA receptor,^{1 2} they have been hypothesized to be of therapeutic value in the setting of focal cerebral ischemia. We recently demonstrated that the potent -ligand PPBP³ prevents early evidence of brain injury in a well-characterized cat model of transient focal ischemia.⁴ In this previous study, we determined that the mechanism of protection afforded by PPBP was not related to a more favorable redistribution of blood flow. However, because of the short duration of reperfusion (4 hours), we could not determine whether PPBP affected the volume of brain infarction or just the rate of brain injury development.⁵ Therefore, in the present study, we tested whether treatment with PPBP in a rat model of transient focal cerebral ischemia would affect the volume of brain infarction measured at 22 hours of reperfusion.

	Materials and Methods

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The study was conducted in accordance with National Institutes of Health guidelines for the use of experimental animals, and the protocols were approved by the institutional animal care and use committee.

Male rats weighing 300 to 385 g (n=25) were anesthetized with halothane in oxygen. Anesthesia was maintained with 1.0% to 1.5% inspired halothane via spontaneous ventilation using a face mask in oxygen-enriched air. Rectal temperature was maintained at 37.0±0.5°C throughout the surgical procedures with a heat lamp. The right femoral artery was cannulated to measure mean arterial blood pressure, PaO₂, PaCO₂, and pH. The right femoral vein was cannulated for administration of fluids and drugs. After cannulation, both catheters were exteriorized in the posterior mid-thorax.

Transient focal ischemia was produced using a model of intraluminal occlusion.^{6 7 8} Briefly, the right common carotid artery was exposed through a midline incision, and the external carotid artery was ligated. The occipital artery branch of the external carotid artery was coagulated, and the internal carotid artery was carefully separated from the vagus nerve. The pterygopalatine artery was ligated with a 4-0 silk suture close to its origin. Ischemia was produced by advancing a 4-0 monofilament nylon suture (Ethilon), with its distal tip rounded by application of heat, as far as 20 mm into the internal carotid artery. After placement, the intravascular suture was secured with a 6-0 silk suture tied around the internal carotid artery. Although cerebral blood flow was not measured in the present study, the length of suture required to block the middle cerebral artery was determined in a preliminary study of 50 rats. In these preliminary studies, each rat was killed after suture placement, and proper tip location at the origin of the middle cerebral artery was visually confirmed.

Arterial blood pressure was continuously monitored during experimental preparation, ischemia, and the first hour of reperfusion. Arterial pH, PaCO₂, PaO₂, hemoglobin level, and blood glucose concentration were measured as previously described.⁴

Anesthesia was terminated 10 minutes after placement of the intravascular ligature. Neurological evaluation⁸ was performed at 45 minutes of ischemia to assess adequacy of occlusion. Five rats were excluded from the protocol, before drug administration, because of inadequate neurological evidence of ischemia (no spontaneous circling or contralateral weakness). At 1 hour of ischemia, rats were randomly assigned to receive an infusion of either saline (diluent) or 1 µmol/kg per hour of PPBP at 0.5 mL/h. This dose was chosen because it was therapeutic in a cat model of transient focal ischemia.⁴ At 2 hours of ischemia, the rats were reanesthetized with halothane, and the intraluminal nylon suture was removed until the distal tip became visible at the origin of the internal carotid artery. Each infusion continued throughout 22 hours of reperfusion.

At the end of reperfusion, the rats were reanesthetized with halothane and decapitated. The brain of each animal was then removed and cut into 2-mm-thick sections from the frontal pole and placed in a 2% solution of TTC (Sigma Chemical Co) in saline at 37°C for 30 minutes.

Values are expressed as mean±SEM. Statistical comparison to assess changes in measured physiological variables within groups was performed by repeated measures ANOVA. Comparison of physiological variables, blood flow, and injury volume between groups was achieved with one-way ANOVA. Post hoc analysis was performed with the Newman-Keuls test. Two-way ANOVA (brain section and treatment group) was used to determine the effect of drug treatment on regional injury volume. Statistical differences were considered significant at P<.05.

	Results

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There were no significant differences in any physiological variables between the experimental groups (Table, Fig 1). In both groups there was a small but statistically significant increase in arterial pH and decreases in PaCO₂, PaO₂, and arterial glucose concentration during ischemia (Table). During reperfusion, discontinuation of anesthesia resulted in an increase in mean arterial blood pressure compared with baseline (anesthetized) values in both groups (Fig 1).

View this table: [in this window] [in a new window]   Table 1. Arterial Blood Gas and Glucose Values in Rats During Baseline, Ischemia, and Reperfusion in Control and PPBP Groups

View larger version (20K): [in this window] [in a new window]   Figure 1. Mean arterial blood pressure and body temperature in rats treated with an intravenous infusion (0.5 mL/h) of either saline (Control) or PPBP (1 µmol/kg per hour) that began at 1 hour of ischemia and continued for 22 hours of reperfusion. The total duration of ischemia was 2 hours. Values are mean±SEM, n=10 for each group. *P<.05 vs baseline value. There were no differences between groups.

When infarction volume was analyzed separately for each of seven coronal sections, infarction was smaller in ipsilateral cerebral cortex (group-slice interaction, P<.05) and striatum (group effect and group-slice interaction, P<.001) in the PPBP group than in saline controls (two-way ANOVA) (Fig 2). In addition, total infarction volume in the striatum was smaller (P<.01) in PPBP-treated (19±4 mm³) than in control (44±4 mm³) rats. However, because of variability within groups, the effect of PPBP to reduce total ipsilateral cortex infarction volume (control, 136±27; PPBP, 80±28 mm³) did not reach statistical significance (P=.16).

View larger version (21K): [in this window] [in a new window]   Figure 2. Injury volume of ipsilateral striatum and cerebral cortex in rats exposed to 2 hours of focal cerebral ischemia and 22 hours of reperfusion. Rats were treated with an intravenous infusion (0.5 mL/h) of either saline (Control) or PPBP (1 µmol/kg per hour) that began at 1 hour of ischemia and continued for 22 hours of reperfusion. Values are expressed as volume of injury in each 2-mm coronal section (mean±SEM). Section 1 was the most the anterior and Section 7 was the most posterior. Two-way ANOVA demonstrated a difference between groups in both regions.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References Introduction  References

 
This study demonstrates that intravenous administration of PPBP substantially reduces the volume of brain infarction in rats subjected to transient focal ischemia. These results support a therapeutic role for acute administration of -receptor ligands in the setting of transient focal ischemia. In our previous study, PPBP prevented early evidence of brain injury in a model of transient focal ischemia in cats.⁴ However, this previous study left open the possibility that PPBP only affected the rate of development of brain injury rather than long-term neurological outcome. We conclude from the present study that PPBP prevents brain infarction rather than simply delaying evolution of injury in the setting of transient focal cerebral ischemia.

The role of -receptors in the mechanism of ischemic brain injury has not been completely elucidated. One of the major difficulties in defining a role for -receptor ligands is that there are few pharmacological agents that have effects that are isolated to the -receptor. For example, some -receptor ligands interact at a number of different receptors, including the NMDA receptor complex.^{9 10 11} Additional confusion arises from the finding that several pharmacological agents that were originally believed to have neuroprotective properties exclusively because of effects at the NMDA receptor¹² have also been found to be potent -receptor ligands at 37°C.³ One of these agents, ifenprodil, reduces brain injury in a model of permanent focal ischemia in cats^{13 14} by minimizing brain edema without an alteration in cerebral perfusion.¹⁴

A variety of -receptor ligands have also been evaluated in a gerbil model of transient ischemia. For example, (+)SKF 10,047, a -ligand that is also a noncompetitive NMDA receptor antagonist,^{10 11} is neuroprotective in a gerbil model of transient focal ischemia.^{15 16} The mechanism of protection by (+)SKF 10,047 may be related to its ability to prevent ischemia-induced increases in intracellular calcium¹⁵ or its ability to prevent cortical spreading depression.¹⁷ In addition, several drugs in a series of U-50,488H analogues, which are potent -receptor ligands, manifested significant efficacy in the gerbil model of transient ischemia, whereas one compound in the series (BD-601) afforded no neuroprotection despite marked affinity for -receptors.¹⁸ Factors that may influence the effects of -receptor ligands in models of cerebral ischemia include differential activities of these drugs at -receptor subtypes^{19 20} and interactions with neurotransmitter systems not directly related to -receptors. Furthermore, although most evidence suggests that -receptor ligands act similarly as agonists, some reports suggest antagonist actions of -compounds.¹⁹

Several -receptor ligands have been found to protect from glutamate, NMDA, and hypoxia-induced neurotoxicity in neuronal cultures,^{1 2} suggesting that the mechanism of protection during ischemia is mediated postsynaptically at the NMDA receptor. In addition, degree of ligand affinity for the phencyclidine site of the NMDA receptor correlated with ability to attenuate NMDA-mediated neurotoxicity.² However, -receptor ligands, with negligible affinity for the NMDA receptor, have also been shown to inhibit ischemia-induced glutamate release from hippocampal slices.²¹ Thus, it is also possible that -receptor ligands protect neurons during ischemia by simply decreasing extracellular concentrations of excitatory amino acids. It follows that the in vitro protective effects of -receptor ligands, which do not have actions at the NMDA receptor, may protect neurons from injury during hypoxia by a mechanism that is mediated presynaptically.

There is concern that noncompetitive NMDA receptor antagonists and phencyclidine produce vacuoles and induce the hsp70 messenger RNA and HSP70 stress protein.²² It has been proposed that phencyclidine causes depolarization of neurons, which produces very high intracellular calcium levels and neuronal injury by a mechanism involving blockade of potassium channels that may be linked to -receptors. However, we believe that it is necessary to separately evaluate agents such as PPBP, which appear to work by a mechanism different from MK-801 and phencyclidine.

In conclusion, PPBP is effective in decreasing brain injury from transient focal ischemia, even when it is administered after the onset of ischemia.

	Selected Abbreviations and Acronyms

 

PPBP = 4-phenyl-1-(4-phenylbutyl) piperidine NMDA = N-methyl-D-aspartate TTC = 2,3,5-triphenyltetrazolium chloride (+)SKF 10,047 = N-allylnormetazocine

	Acknowledgments

 
This study was supported by US Public Health Service National Institutes of Health grant NS20020 and by the Division of Intramural Research of the National Institute on Drug Abuse. The authors thank Ying Wu for her excellent technical assistance.

	Footnotes

 
Reprint requests to Jeffrey R. Kirsch, MD, Department of Anesthesiology and Critical Care Medicine, 600 N Wolfe St, Blalock 1410, Baltimore, MD 21287-4963.

Received February 2, 1996; revision received June 3, 1996; accepted July 12, 1996.

	References

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4. Takahashi H, Kirsch JR, Hashimoto K, London ED, Koehler RC, Traystman RJ. PPBP [4-phenyl-1-(4-phenylbutyl) piperidine, a potent -receptor ligand, decreases brain injury following transient focal ischemia in cats. Stroke. 1995;26:1676-1682.[Abstract/Free Full Text]
5. Dietrich WD. Editorial comment on `PPBP [4-phenyl-1-(4-phenylbutyl) piperidine, a potent -receptor ligand, decreases brain injury following transient focal ischemia in cats.' Stroke. 1995;26:1682.
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13. Gotti B, Duverger D, Bertin J, Carter C, Dupont R, Frost J, Gaudilliere B, MacKenzie ET, Rousseau J, Scatton B, Wick A. Ifenprodil and SL 82.0715 as cerebral anti-ischemic agents, I: evidence for efficacy in models of focal cerebral ischemia. J Pharmacol Exp Ther. 1988;247:1211-1221.[Abstract/Free Full Text]
14. Baskaya MK, Rao AM, Donaldson D, Prasad MR, Dempsey RJ. Effect of ifenoprodil on infarct size, blood brain barrier breakdown, and edema formation after focal cerebral ischemia in the cat. Soc Neurosci Abstr. 1995;21:995. Abstract.
15. Lysko PG, Yue T-L, Gu J-L, Feuerstein G. Neuroprotective mechanism of (+)SKF 10,047 in vitro and in gerbil global brain ischemia. Stroke. 1992;23:1319-1324.[Abstract/Free Full Text]
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Editorial Comment

Paul G. Lysko, PhD, Guest Editor

Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References Introduction  References

 
This study has extended previous observations that the -receptor ligand PPBP decreased brain injury 4 hours after transient focal ischemia in cats.^1R In that study, drug treatment was initiated before the end of occlusion and continued throughout the reperfusion period. Since the duration of reperfusion had been brief, the present study has extended the assessment of brain damage in rats until 22 hours after reperfusion. It is an important consideration in treatment models of transient cerebral ischemia that sufficient development of neuronal injury be allowed to be able to assess the value of a particular therapeutic regimen. Constant infusion of PPBP into ischemic rats was shown to produce a significantly smaller infarction volume in the striatum and to reduce total cortical infarction volume as well, indicating that early initiation of treatment and constant infusion are of benefit with this particular compound. As the authors are aware, defining the mechanisms behind the neuroprotective properties of -ligands remains difficult because of cross-reactivities with different receptors and neurotransmitter systems. The substituted piperidine, PPBP, is a potent inhibitor of binding at ₂-sites, yet as the authors point out, although some -ligands have been shown to inhibit events such as glutamate release, it has not been demonstrated that the drugs are acting at -sites. We have recently shown that a substituted piperidine, SB201823-A, is a neuroprotective calcium channel antagonist that halves the total neuronal calcium load initiated by activation of glutamate receptors.^2R This is an example of indirect interference with glutamate excitotoxicity, by a compound acting at a non-NMDA–mediated event. Because side effects have limited the clinical usage of many potentially therapeutic anti-ischemic drugs, it is notable that PPBP causes no significant differences among the physiological variables reported to date. Although its neuroprotective mechanisms may not be elucidated as yet, the lack of side effects noted with PPBP shows the potential for developing more efficacious -ligands for treatment of cerebral ischemia.

	Selected Abbreviations and Acronyms

 

PPBP = 4-phenyl-1-(4-phenylbutyl) piperidine NMDA = N-methyl-D-aspartate TTC = 2,3,5-triphenyltetrazolium chloride (+)SKF 10,047 = N-allylnormetazocine

Values are mean±SEM; n=10 for each group.

*P<.05 vs baseline value. There were no differences between groups at any time in the protocol for these variables.

	References

Top Abstract Introduction Materials and Methods Results Discussion References Introduction  References

 

1. Takahashi H, Kirsch JR, Hashimoto K, London ED, Koehler RC, Traystman RJ. PPBP [4-phenyl-1-(4-phenylbutyl) piperidine], a potent -receptor ligand, decreases brain injury after transient focal ischemia in cats. Stroke.. 1995;26:1676-1682.
2. Barone FC, Lysko PG, Price WJ, Feuerstein G, Al-Baracanji KA, Benham CD, Harrison DC, Harries MH, Bailey SJ, Hunter AJ. SB 201823-A antagonizes calcium currents in central neurons and reduces the effects of focal ischemia in rats and mice. Stroke.. 1995;26:1683-1690.[Abstract/Free Full Text]

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Takahashi, H. Articles by Lysko, P. G. Search for Related Content PubMed PubMed Citation Articles by Takahashi, H. Articles by Lysko, P. G.