(Stroke. 2001;32:1613.)
© 2001 American Heart Association, Inc.
Original Contributions |
Neuroprotective Effect of 
1-Receptor Ligand 4-Phenyl-1-(4-Phenylbutyl) Piperidine (PPBP) Is Linked to Reduced Neuronal Nitric Oxide Production
From the Departments of Anesthesiology and Critical Care Medicine (T.G., S.G., A.B., P.D.H., J.R.K.), Neurology (A.B., J.R.K.), and Neuroscience (V.L.D.), Johns Hopkins University School of Medicine, Baltimore, Md. Drs Goyagi and Goto have contributed equally as primary authors.
Correspondence to Anish Bhardwaj, MD, Neurosciences Critical Care Division, Meyer 8-140, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287. E-mail abhardwa{at}jhmi.edu
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Abstract |
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Background and Purpose—The potent
1-receptor ligand 4-phenyl-1-(4-phenylbutyl)
piperidine (PPBP) provides neuroprotection in experimental stroke. We
tested the hypothesis that PPBP attenuates striatal tissue damage after
middle cerebral artery occlusion (MCAO) by a mechanism involving
reduction of ischemia-evoked nitric oxide (NO)
production. Furthermore, we determined whether the agent fails
to protect ischemic brain when neuronal nitric oxide synthase
(nNOS) is genetically deleted or pharmacologically inhibited (selective
nNOS inhibitor, 7-nitroindazole
[7-NI]). Methods—Halothane-anesthetized adult male Wistar rats were subjected to 2 hours of MCAO by the intraluminal filament occlusion technique. All physiological variables were controlled during the ischemic insult. In vivo striatal NO production was estimated via microdialysis by quantification of local, labeled citrulline recovery after labeled arginine infusion. In a second series of experiments, nNOS null mutants (nNOSKOs) and the genetically matched wild-type (WT) strain were treated with 90 minutes of MCAO. Brains were harvested at 22 hours of reperfusion for measurement of infarction volume by triphenyltetrazolium chloride histology.
Results—PPBP attenuated infarction volume at 22 hours of reperfusion in cerebral cortex and striatum and markedly attenuated NO production in ischemic and nonischemic striatum during occlusion and early reperfusion. Treatment with 7-NI mimicked the effects of PPBP. In WT mice, infarction volume was robustly decreased by both PPBP and 7-NI, but the efficacy of PPBP was not altered by pharmacological nNOS inhibition in combined therapy. In contrast, PPBP did not decrease infarction volume in nNOSKO mice.
Conclusions—These data suggest that the mechanism of neuroprotection of PPBP in vivo is through attenuation of nNOS activity and ischemia-evoked NO production. Neuroprotective effects of PPBP are lost when nNOS is not present or is inhibited; therefore, PPBP likely acts upstream from NO generation and its subsequent neurotoxicity.
Key Words: cerebral ischemia, focal • excitotoxicity • infarction • nitric oxide • receptors, sigma • reperfusion
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Introduction |
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Numerous studies have demonstrated robust neuroprotective properties of
-receptor
ligands in animal models of cerebral
ischemia.1 2 3 4 5 6 7 8
We have previously demonstrated that the potent -receptor ligand
4-phenyl-1-(4-phenylbutyl) piperidine (PPBP)
(1) attenuates infraction volume in
cat6 and
rat3 7 8
after middle cerebral artery occlusion (MCAO). Various antiexcitotoxic
mechanisms for -receptor ligands have been postulated, including
inhibition of ischemia-induced glutamate
release,4 9
attenuated postsynaptic glutamate-evoked
Ca2+
influx,10 11
depressed neuronal responsivity to
N-methyl-D-aspartate
(NMDA) receptor
stimulation,12 13 14
reduced dopamine
neurotransmission,2 and
prevention of cortical spreading
depression.15 In vitro,
-receptor ligands prevent glutamate-induced activation of nitric
oxide synthase
(NOS).16 Nitric oxide
(NO) is an important mediator in ischemic brain
injury.17 18 19
Specifically, NO derived from constitutively expressed NOS in neurons
(nNOS) and the inducible isoform expressed by many cells (iNOS) are
important in excitotoxic injury
cascades.18 19
Pharmacologically selective inhibitors of nNOS and iNOS
attenuate infarction volume after focal cerebral
ischemia.20 21 22 We have previously demonstrated that PPBP infusion into normal striatum by microdialysis attenuates basal, as well as NMDA-evoked, striatal NO production in situ12 and hypothesized that systemic PPBP treatment could reduce stroke damage by preventing ischemia-induced NO production. If so, then this action would disrupt neuronal death pathways that ordinarily result from ischemic depolarization, glutamate transmitter release, NMDA ionotropic receptor stimulation, and downstream nNOS activation. The present study tested this hypothesis. First, we determined whether PPBP attenuates striatal tissue damage in rat after MCAO and whether reduced infarction is accompanied by local depression of ischemia-evoked NO production. Second, we determined whether PPBP fails to protect ischemic brain when nNOS is either genetically deficient (nNOSKO) or pharmacologically inhibited (7-nitroindazole [7-NI]). If so, then these combined results would strongly implicate neuronal NO as an important target in the neuroprotective mechanism(s) of PPBP.
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Materials and Methods |
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Experimental protocols were approved by the Institutional Animal Care and Use Committee and conform to the National Institutes of Health guidelines for the care and use of animals in research. All methods have been previously described in rat3 7 8 23 24 and mouse.25 26 27
Rat MCAO, Cerebral Microdialysis, and NOS
Activity
Femoral arterial and venous catheters
were placed in halothane-anesthetized male Wistar rats (weight,
300 to 350 g; n=51). Both catheters were exteriorized in mid
thorax and fixed onto a swivel to allow for free postoperative
movement. Physiological levels of
arterial blood gases were maintained throughout the
experiments; rectal and temporalis muscle temperature was maintained at
38±0.5°C with a heating lamp throughout the surgical
procedures.
Dialysis probes used in these studies were constructed as described previously.12 24 28 29 30 Recovery across the dialysis probe is approximately 15% in vitro. Microdialysis cannulas were stereotaxically placed into striatum (0.5 mm anterior and 2.5 mm lateral to the bregma; depth 6 mm from the dura)31 and fixed in position as previously described.12 24 After a 60-minute postsurgical equilibration period, cannulas were perfused with 3 µmol/L [14C]L-arginine in artificial CSF (aCSF) at 1 µL/min. Effluent samples (20 µL) were collected in 20-minute epochs for 2 hours ("preloading" with [14C]L-arginine), 2 hours of MCAO, and 3 hours of reperfusion and assayed for [14C]L-citrulline content and compared on a paired basis (right versus left striatum in each animal). NO production was measured as described by Bredt et al32 with some modifications,12 24 28 29 30 with the premise that arginine is converted to equimolar citrulline and NO via NOS.36 The efficiency of arginine trapping is approximately 99%, and that of citrulline flow-through is 92% to 96%.
Rats were then subjected to transient focal ischemia (120 minutes) by MCAO with an intraluminal filament technique, as previously described.3 7 8 23 24 33 Adequacy of occlusion and reperfusion was confirmed by laser-Doppler flowmetry (LDF) over ipsilateral parietal cortex (model MBF3D, LDF, Moor instruments Ltd). Rats that did not demonstrate significant reduction to at least 40% of baseline signal during MCAO or rapid restoration of the LDF signal during reperfusion were excluded. LDF measurements were recorded at 15, 30, 60, 90, and 120 minutes after MCAO, immediately and 5, 10, 30, 60, 120, 150, and 180 minutes of reperfusion. Rats were then allowed to awaken from anesthesia (total anesthesia time, approximately 9 hours).
Rats were randomized to 1 of 5 treatment groups: (1) continuous intravenous saline in surgical shams (n=4); (2) vehicle for nNOS inhibitor, 7-NI (1 mL peanut oil:dimethyl sulfoxide [DMSO] 50:50) given intraperitoneally 30 minutes before MCAO followed by saline infusion (n=10); (3) 7-NI 50 mg/kg IP 30 minutes before MCAO followed by saline infusion (n=10); (4) 7-NI 100 mg/kg IP 30 minutes before MCAO followed by saline infusion (n=5); and (5) vehicle for 7-NI given intraperitoneally before MCAO followed by PPBP intravenous infusion (1 µmol/kg per hour) (n=10). All infusions were at a rate of 0.5 mL/h. At 3 hours of reperfusion, rats were recovered and received ad libitum access to food and water. At 22 hours of reperfusion, brain was harvested under anesthesia and sliced into seven 2-mm-thick coronal sections for staining with 1% triphenyltetrazolium chloride (TTC) in saline at 37°C for 30 minutes.3 7 8 23 24 Infarction volume was measured by digital imaging (MTI Series 68 Video Camera) and image analysis software (SigmaScan Pro, Jandel). The infarcted area was integrated across sections and over the entire ipsilateral hemisphere. Infarction volumes were determined in cortex and striatum and expressed as a percentage of the volume of the ipsilateral structure.3 7 8 23 24 Microdialysis probe placement was confirmed within the area of TTC-determined infarction.
MCAO in Mice
Male nNOSKO and wild-type C57Bl/6 (WT) mice (weight,
21.1 to 28.5 g) were subjected to reversible
MCAO.25 26 27
The nNOSKO mice were produced on a purebred C57Bl/6 background as
previously described.34 Mice
were anesthetized with 1% to 1.2% halothane in
oxygen-enriched air, and rectal and temporalis muscle temperatures were
controlled at 37±0.5°C. In separate cohorts of mice (3 per treatment
group), arterial blood pressure, blood gases, and cortical
LDF were determined during MCAO and 30 minutes of
reperfusion.25 26 27
MCAO was verified by allowing the animal to waken, and neurological
deficit scoring was performed as follows: 0=normal motor function;
1=flexion of torso and of contralateral forelimb on tail lift;
2=circling to the contralateral side but normal posture at rest;
3=leaning to contralateral side at rest; and 4=no spontaneous motor
activity. Mice with clear neurological deficits (neurological deficit
scoring 
2) were reanesthetized for withdrawal of the suture
and reperfusion after 90 minutes of MCAO. At 22 hours of reperfusion,
brains were harvested for assessment of injury volume. The forebrain
was sliced into five 2-mm-thick coronal sections and stained with 1%
TTC; total infarction volume was again determined by image
analysis.
Each group of mice was treated with an intraperitoneal injection of either 0.1 mL 7-NI (25 mg/kg) or vehicle (0.09 mL peanut oil+0.01 mL DMSO) at 5 minutes after MCAO. Each animal received either PPBP (10 µmol/kg per hour) or vehicle (intravenous saline) at 60 minutes of MCAO and continued for 23 hours (0.1 mL/h) via lateral tail venous catheter. Therefore, 6 groups were examined: (1) WT, intraperitoneal vehicle plus intravenous saline; (2) WT, 7-NI vehicle plus PPBP; (3) WT, 7-NI plus saline; (4) WT, 7-NI plus PPBP; (5) nNOSKO, vehicle plus saline; and (6) nNOSKO, vehicle plus PPBP.
Materials
[14C]L-arginine
(317 mCi/mmol) was obtained from Amersham, and
7-NI, DMSO, and peanut oil were obtained from
Sigma Chemical. PBBP was a generous gift from
National Institute for Drug Abuse.
Statistical Analysis
Within each experimental group, the effluent
citrulline recovery was analyzed by 2-way ANOVA; effluent
citrulline from the 2 striata (ischemic versus
nonischemic) was analyzed as the within-subjects factor
and the 20-minute collections as a second within-subjects factor.
Infarction volume and physiological data between
and within groups were analyzed by 2-way ANOVA with Fisher’s
post hoc test. A value of
P<0.05 was considered
significant. Data are presented as
mean±SEM.
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Results |
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MCAO in Rats
Table 1
summarizes physiological
data. Premature mortality was 3 of 15 in saline-treated controls, 1 of
11 in PPBP-treated animals, and 5 of 15 in 50 mg/kg 7-NI–treated rats.
Two rats were excluded from the saline control group because the
residual LDF signal did not decrease to 40% of baseline signal and did
not remain below this value during MCAO. Reduction of the LDF signal
during MCAO and reperfusion was not different among treatment groups.
Infarction volume was reduced with PPBP (cortex, 14.2±4.6%; striatum,
25.0±5.1%), as well as 7-NI 50 mg/kg (cortex, 15.6±5.2%; striatum,
18.7±3.8%) and 7-NI 100 mg/kg (cortex, 7.0±5.3%; striatum,
19.4±4.1%) compared with saline (cortex, 40.0±8.7%; striatum,
58.6±5.7%; P<0.05)
(Figure 1).
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As expected, labeled citrulline recovery increased
bilaterally in all treatment groups. Surgical shams did not demonstrate
differences in recovery in the 2 striata
(Figure 2A). Citrulline recovery markedly increased in
ischemic striatum compared with contralateral striatum in
controls
(Figure 2B). Citrulline recovery was attenuated in
ischemic striatum in rats treated with 7-NI (50 and 100 mg/kg)
(Figure 3). PPBP and 7-NI (100 mg/kg) also markedly
attenuated labeled citrulline recovery in ischemic and
nonischemic striata
(Figure 4).
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MCAO in Mice
Premature mortality was 2 of 12 mice in WT-vehicle, 2
of 11 in WT-PPBP, 2 of 10 in WT-7-NI, 2 of 11 in WT-7NI+PPBP, 1 of 10
in nNOSKO-vehicle, and 0 of 10 in nNOSKO-PPBP groups. Two of 12 mice in
WT-vehicle, 1 of 11 in WT-PPBP, 1 of 11 in WT-7-NI+PPBP, and 1 of 10 in
nNOSKO-vehicle groups were excluded because of
intracerebral and subarachnoid
hemorrhage. Thus, 8 mice per group were included in the final
analysis. WT mice used for the measurement of
physiological variables were somewhat larger
(weight, 27.6±0.7 g; n=12) than nNOSKO mice (weight, 23.0±0.4 g; n=6;
P<0.001). Rectal and
temporalis muscle temperature and blood pressure were recorded
every 10 minutes during ischemia and averaged to a single
number and recorded as the value during MCAO. These same
variables were recorded at 5, 10, 20, and 30 minutes of
reperfusion and averaged to a single number and recorded as the
value during reperfusion. To simplify data presentation,
Table 2 shows averages at each experimental period.
Reduction of LDF signal during MCAO was not different between
experimental groups. The neurological deficit score was not different
among treatment groups after MCAO.
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As expected, infarction volume was reduced in
vehicle-treated nNOSKOs compared with vehicle-treated WT
(Figure 5). PPBP did not decrease infarction size when
administered to nNOSKO mice (31.5±7.5% versus 31.4±7.0%)
(Figure 5). In contrast, infarction size (62.6±6.9%) was
robustly decreased by PPBP (33.4±4.9%;
P<0.05) compared with
vehicle-treated WT mice. 7-NI also provided protection in WT MCAO
(37.3±7.8%; P<0.05);
however, there was no additive effect of combined therapy
(35.1±7.4%).
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Discussion |
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There are 2 significant findings in this study of the prototypic
1-receptor ligand PPBP and
experimental stroke. First, PPBP markedly attenuates infarction volume
and ischemia-evoked labeled citrulline recovery in rat striatum
compared with saline-treated controls, and 7-NI mimics these actions.
Second, PPBP attenuates infarction volume in mice, demonstrating that
the agent is effective in both rat and mouse. However, while PPBP
effectively protects WT brain, it confers no benefit in nNOSKO animals
and does not accentuate neuroprotection produced by 7-NI in
WT.
We have previously demonstrated that the
1-ligand prototype PPBP provides
neuroprotection in several animal models of transient focal cerebral
ischemia.6 7
Widespread but heterogeneous labeling of -receptors has
been reported in brain,35
particularly in sterol-producing brain
region.36 Numerous
mechanisms have been proposed for the neuroprotective effects of
-ligands. Using our present microdialysis technique, we showed
that local PPBP administration into striatum rapidly suppresses
NMDA-induced citrulline recovery in the
effluent.12 Accordingly, we
and others have postulated that -receptors may act in some way to
modulate signal transduction between NMDA receptor and NOS
activation.12 16
For example, -ligands reduce NMDA-induced increases in intracellular
Ca2+,10 11
which could influence Ca2+-dependent NOS
activation. Interactions between PPBP and non-NMDA receptors with
permissive Ca2+ entry have also been
reported,37 including
modulation of metabotropic glutamate receptors and phospholipase
C,38 resulting in reduced
mobilization of Ca2+ stores, which, in cells
containing NOS, could attenuate NO production. Alternatively,
presynaptic mechanisms may be important. If PPBP attenuates glutamate
release following cerebral
ischemia4 9
with less consequent NMDA receptor stimulation in NOS-positive neurons,
then the net result would be decreased NOS activity.
Although the present results do not clarify the precise mechanism(s) by which PPBP alters ischemic NO production, it is clear that this effect does occur and corresponds to regional reduction of ischemic cell death in striatum. Excessive NO and NO toxicity play a significant role in ischemic neuronal injury,18 19 and pharmacological inhibition of nNOS attenuates infarction volume.19 21 22 39 Accordingly, we compared PPBP with a well-studied, selective nNOS inhibitor, at doses previously found to be neuroprotective,21 and found similar reduction in infarction volume and ischemic labeled citrulline recovery in PPBP- and 7-NI–treated animals. With 50 mg/kg 7-NI pretreatment in rats, the time-dependent increase in labeled citrulline recovery was attenuated in ischemic striatum. There was further attenuation in absolute labeled citrulline recovery with 100 mg/kg 7-NI pretreatment, indicating a dose-response relationship. Citrulline recovery in our technique is a reflection of total NO from endothelial and neuronal sources. Because 7-NI attenuated citrulline recovery, it seems likely that neuronal sources predominate in our assay. Continuous infusion of PPBP during MCAO also markedly attenuated labeled citrulline recovery throughout striatum.
As in previous reports,19 40 nNOS null mice sustained reduced infarct volumes compared with WT controls. We reasoned that if PPBP acted via nNOS-linked mechanisms, then the agent could have no effect on stroke outcome in nNOSKOs and would add little to the efficacy of 7-NI in WT mice. 7-NI has not been well studied in mouse; however, we chose a dose (25 mg/kg) previously reported to reduce NO activity in rat brain.21 We observed solid reduction of ischemic damage in the WT, but combination therapy (PPBP and 7-NI) did not produce additive protection. Furthermore, PPBP had no efficacy in nNOSKOs. As with any transgenic species that has developed throughout life with a genetic mutation, we acknowledge the possibility of unique compensatory responses in nNOSKOs that may have obscured the benefit of PPBP. The present findings implicate nNOS activity as a key link to the mechanism of action of PPBP in ischemic brain. Other isoforms of NOS, eg, the Ca2+-independent inducible isoform of NOS, are expressed by neurons, endothelial cells, and microglia19 41 42 and clearly play a role in stroke outcome. Treatment with selective inhibitors42 or genetic deletion20 of iNOS improves infarct volume. Effects of PPBP on iNOS activity are unknown at present, and these experiments were not designed to specifically exclude interactions between PPBP and iNOS. However, it seems unlikely that iNOS activity contributed to citrulline recovery in the rat experiments. We monitored in vivo NOS activity for up to 5 hours after MCAO in these animals by microdialysis and detected large increases in citrulline recovery by 1 hour of MCAO. The steady production of labeled citrulline persisted throughout the 5-hour monitoring period. Such an acute time frame of NO production would be too early to reflect iNOS activity. However, histological tissue outcome was determined at 22 hours of reperfusion, a time frame in which iNOS activity contributes to cell death. Therefore, we cannot exclude the possibility that PPBP influences iNOS as well as nNOS-linked mechanisms.
In this series of experiments, the 3-mm tips of the microdialysis probes that constitute the active region of dialysis43 were localized in the striatum, as confirmed by postmortem brain dissection. The striatum is highly vulnerable to cerebral ischemia44 and constitutes the ischemic core in our rat model of MCAO. Abundant synthetic mechanisms for NO have been demonstrated in striatum.12 As described previously,12 we have used labeled citrulline recovery as an indirect measure of NO production in vivo. MCAO in the rat enhances labeled citrulline recovery in the ischemic striatum, which is attenuated by local infusion of the NOS inhibitor L-nitroarginine,24 thereby reflecting increased NO production. The time-dependent increase in recovery of citrulline with control perfusion with aCSF is presumed to reflect a dynamic and complex kinetic process involving diffusion of labeled arginine across the dialysis membrane, its cellular uptake and efflux, and diffusion of labeled citrulline back to and across the dialysis membrane.12 28 29 30 In the present study the 2-hour "loading" period (first 6 microdialysate collections) with labeled arginine allowed differences between labeled citrulline recovery to be detected between striatum within 20 minutes after MCAO. This response is consistent with the rapid increase in labeled citrulline recovery after NMDA infusion12 and decreases in cGMP in microdialysates reported with nitroarginine infusion.45
We used bilateral microdialysis perfusion in a paired experimental design to reduce interanimal variability arising from physiological factors such as arterial blood pressure, blood gases, and depth of anesthesia. Although the 51 rats used in this study were randomly assigned to the 5 experimental groups, some variability in labeled citrulline recovery may have arisen from using a different lot of labeled arginine and Dowex resin. Differences in the absolute levels of basal citrulline recovery are evident between different groups receiving similar interventions. Some of this variability may be due to differences in the efficiency of arginine trapping by the Dowex column and due to biological variability secondary to differences in infarction volume in the striatum. Variability may also arise from tissue injury resulting from placement of a 300-µm diameter probe. Citrulline recovery occurs in brain proximate to the microdialysis probe. With the use of autoradiography, labeled arginine infused at a rate of 1 µL/min via the microdialysis probe spreads in a 3-mm cylinder by 1 hour of infusion30 ; further diffusion is limited, possibly because of cellular uptake.
In conclusion, this study demonstrates that like 7-NI, PPBP pretreatment affords significant neuroprotection in cortex and striatum after transient focal ischemia and reperfusion in rat and mouse. We have previously demonstrated that PPBP administered 60 minutes after occlusion provides neuroprotection that is clinically relevant; however, a preischemic treatment paradigm was used here to elicit maximal effect on NOS activity. Ischemia-evoked NO production was markedly attenuated by both 7-NI and PPBP. Neuroprotective PPBP did not amplify acute or chronic nNOS inhibition. Therefore, we conclude that PPBP acts by a mechanism upstream from neuronally generated NO toxicity.
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Acknowledgments |
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This work was supported in part by US Public Health Service National Institutes of Health grants NS20020 and NS33668. Dr Bhardwaj is supported in part by the Established Investigator Grant from the American Heart Association. The authors thank Edythe D. London for providing
1-receptor ligand PPBP used in this
study. Received January 24, 2001; revision received February 26, 2001; accepted March 12, 2001.
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