Published online before print March 18, 2004, doi: 10.1161/01.STR.0000125011.93188.c6
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(Stroke. 2004;35:1180.)
© 2004 American Heart Association, Inc.
Original Contributions |
Prolonged Opportunity for Ischemic Neuroprotection with Selective 
-Opioid Receptor Agonist in Rats
From the Departments of Anesthesiology/Critical Care Medicine (T.-Y. C., T.G., T.J.K.T., J.R.K., P.D.H., R.C.K., A.B.) and Neurology (A.B.), Johns Hopkins University School of Medicine, Baltimore, Md; Department of Anesthesiology and Peri-operative Medicine (J.R.K., P.D.H.), Oregon Health and Science University, Portland, Ore.
Correspondence to Dr Anish Bhardwaj, Neuroscience/Critical Care Division, Meyer 8-140, Johns Hopkins Hospital, 600 N Wolfe Street, Baltimore, MD 21287. E-mail abhardwa{at}jhmi.edu
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Abstract |
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Background and Purpose— We have previously demonstrated that pretreatment with selective
-opioid agonist BRL 52537 hydrochloride [(±)-1-(3,4-dichlorophenyl) acetyl-2-(1-pyrrolidinyl) methylpiperidine], provides ischemic neuroprotection following transient focal ischemia in rats. The present study was undertaken to a) define "therapeutic opportunity" for ischemic neuroprotection with BRL 52537, and b) determine if BRL 52537 attenuates ischemia-evoked efflux of dopamine and its metabolites in the striatum in vivo following transient focal ischemia. Methods— Using the intraluminal filament technique, halothane-anesthetized male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion (MCAO). In a blinded, randomized fashion, rats were treated with saline (vehicle) or 1 mg/Kg/hr BRL 52537 infusion for 22 hours, initiated at onset, 2, 4, or 6 hours of reperfusion (Rep). In a separate set of experiments utilizing in vivo microdialysis, extracellular levels of dopamine and its metabolites were determined in the striatum during 2 hours of MCAO and 3 hours of reperfusion.
Results— Infarct volume (% of contralateral structure; mean ±SEM) in cortex was significantly attenuated when BRL 52537 was administered at reperfusion (22±6%), 2 hours (21±6%), and 4 hours (18±5%) compared with controls (39±5%). In striatum, infarct volume was significantly attenuated when BRL 52537 was administered at reperfusion (38±9%), 2 hours (40±8%), 4 hours (50±8%), and 6 hours (46±9%) as compared with controls (70±4%). A 6- to 8-fold increase in dopamine in microdialysates occurred within 40 minutes of MCAO. Pretreatment with BRL 52537 did not alter microdialysate levels of dopamine or its metabolites in the striatum during MCAO and early reperfusion, as compared with saline controls.
Conclusions— These data demonstrate that BRL 52537 provides robust ischemic neurprotection with a long therapeutic opportunity (at least 6 hours) without altering ischemia-evoked efflux of dopamine (DA) and its metabolites in striatum during ischemia and early reperfusion.
Key Words: infarct • ischemia • kappa(1) opioid receptors • neuroprotection • reperfusion
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Introduction |
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-opioid receptors (KOR) have been shown to play an important role in modulating ischemic brain injury. Several studies have demonstrated that KOR agonists attenuate histological brain injury,1–3 as well as improve functional recovery in animal models of global and focal cerebral ischemia.4,5 We have previously shown that the selective KOR agonist, BRL 52537 provides significant neuroprotection when given as a pretreatment as well as when started at the onset of reperfusion (Rep) in the rat model of middle cerebral artery occlusion (MCAO).6
There is experimental evidence that KOR agonists may provide a prolonged therapeutic window for ischemic neuroprotection. For example, Baskin et al3 demonstrated ischemic neuroprotection in cats with 3 different KOR agonists when drugs were started 6 hours following vascular occlusion and continued with slow-release osmotic pumps for continuous drug delivery for 7 days. In mice, opioid receptor binding studies using focal cerebral ischemia suggest that KOR binding is preserved for long time periods (12 to 48 hours), more so than 
-and µ-opioid receptors,7 suggesting a potentially long therapeutic window.
Previous studies have demonstrated the effects of KOR agonists on a variety of neurotransmitter systems.8–11 Signaling mechanisms utilized by KORs under normal conditions or during neuroprotective actions are not well established. In vivo studies have demonstrated that KOR agonists modulate dopaminergic neurotransmission in the substantia nigra, the neostriatum, and the mesolimbic system.8–11 We have previously demonstrated that BRL 52537 [(±)-1-(3,4-dichlorophenyl) acetyl-2-(1-pyrrolidinyl) methylpiperidine] attenuates ischemia-evoked nitric oxide (NO) production in the striatum in vivo and have postulated that this may account for its neuroprotective action.6
While the cascade of excitotoxic mechanisms during cerebral ischemia is complex, catecholamines likely play an important role in the propagation of brain injury following cerebral ischemia.12,13 For example, previous studies have demonstrated a greater susceptibility of dopaminergic nerve terminals to ischemic injury.13–15 Amelioration of histopathological injury following cerebral ischemia has been demonstrated following attenuation of ischemia-induced surges in extracellular dopamine (DA) with pharmacological agents12,16 as well as surgically by nigrostriatal lesioning.17
In the present study, we sought to determine the "therapeutic window" for ischemic neuroprotection with the highly selective KOR agonist, BRL 52537 hydrochloride ((±)-1-(3,4-dichlorophenyl) acetyl-2-(1-pyrrolidinyl) methylpiperidine),18,19 in a well-characterized model of transient focal ischemia with MCAO in rats. Furthermore, we used in vivo microdialysis to test the hypothesis that BRL 52537 provides neuroprotection by attenuating the acute release and accumulation of extracellular DA in the caudoputamen (CP) complex following transient MCAO.
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Materials and Methods |
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MCAO Model
All experimental protocols were approved by the Institutional Animal Care and Use Committee and conformed to the National Institutes of Health guidelines for the care and use of animals in research. All techniques are as previously described.20,21 In brief, adult male Wistar rats (250 to 300 g; Harlan, Indianapolis, Ind) were anesthetized with halothane (1.0% to 2.0%) in air and allowed to ventilate spontaneously. Concentration of inspired oxygen was adjusted between 25% to 30% to maintain PaO2 between 100 to 150 mm Hg. Using aseptic surgical techniques, the right femoral artery was cannulated to monitor arterial blood pressure and arterial blood gases. The femoral vein was cannulated, tunneled subcutaneously and exteriorized for vascular access and drug administration.20,21 Rectal temperature was maintained throughout surgical procedures, during ischemia until emergence from anesthesia. Transient focal ischemia (2 hours) was produced by MCAO using an intraluminal suture technique in combination with laser-Doppler flowmetry (LDF) (Model MBF3D, Moor Instruments Ltd.) as previously described.20,21
All experiments were performed in a blinded, randomized fashion. Rats were treated with continuous intravenous infusion of vehicle (saline) or 1 mg/Kg/hr BRL 52537 (Research Biochemical International) at onset (Rep-BRL), 2 hours (2 hr-BRL), 4 hours (4 hr-BRL) or 6 hours (6 hr-BRL) of reperfusion, and continued for 22 hours. All infusions were at a rate of 0.3 mL/hr. In all experiments, rats were allowed to emerge from anesthesia at 15 minutes of reperfusion. Following treatments for 22 hours, the femoral venous catheter was ligated and removed. Rats were housed in separate cages at room temperature (22 to 24°C) during emergence from anesthesia and thereafter, until they were euthanized. Neurologic examination21 was performed daily to assess a neurological deficit score (NDS) comprised of the following: consciousness: 0–normal, 1–restless, 2–lethargic, 3–stuporous; gait: 0–normal, 1–paw adduction; 2–unbalanced walking, 3–circling, 4–unable to stand, 5–no movement; limb tone: 0–normal; spastic: 2–flaccid; and pain reflex: 0–normal, 2–hypoactive; 4–absent. A higher NDS indicates poor neurologic status. On day 4 of reperfusion, rats were deeply anesthetized with 5% halothane and decapitated. The brain was harvested and sliced into seven 2-mm thick coronal sections for staining with 1% triphenyltetrazolium chloride (TTC) as previously described.20,21 Infarct volume was measured by using digital imaging. The infarcted area was numerically integrated across each section and over the entire ipsilateral hemisphere. Infarct volumes were measured separately in cerebral cortex and CP complex, expressed as a percentage of the contralateral structure volume, and corrected for swelling as previously described.20,21
Microdialysis
Cerebral microdialysis experiments were performed as described previously.6,20 A microdialysis cannula (membrane length: 3 mm; cutoff: 6 KDaltons; CMA/Microdialysis AB, Stockholm, Sweden) was placed into the right CP complex using stereotactic surgery.20 A 2-hour post-surgical equilibration period was given before the experiment began. Microdialysis cannula was then perfused with artificial cerebrospinal fluid at 1 µL/min. Rats were randomized to receive either an intravenous infusion of 1 mg/Kg/hr BRL 52537 or saline that was initiated 30 minutes prior to MCAO. Microdialysates were collected in epochs of 20 minutes and stored at –80°C. Brains were harvested at 22 hours of reperfusion, sectioned for confirmation of microdialysis probe position and for analysis of infarction volume with TTC staining.
High Performance Liquid Chromatography (HPLC) Measurements
Chromatographic conditions for measurement of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovallinic acid (HVA) in microdialysates were performed using HPLC with electrochemical detection (EC) as previously described.20,22 The detection limit for DA was 2 nmol/L.
Statistical Analysis
Physiological parameters and mean LDF measurements among groups were subjected to repeated-measures ANOVA. Differences in infarct volume were determined by 1-way ANOVA. Post hoc analysis comparisons were made with the Newman-Keuls test. Data are presented as mean±SEM. NSD score is presented as median (with 25% and 75% quartiles) and analyzed by the nonparametric Mann-Whitney U test. For microdialysis experiments, DA and its metabolites in microdialysates within groups were analyzed by 2-way ANOVA.
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Results |
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MCAO Experiments with Prolonged Reperfusion
Mortality rate prior to completion of the experimental protocol (4 days following MCAO) was as follows: 7/21 in controls (one with focal hemorrhage in infarct), 1/8 in 2 hr-BRL group with subarachnoid hemorrhage (SAH), 5/15 in 4 hr-BRL group (one with SAH), 4/11 in 6 hr-BRL group (2 with focal hemorrhages in the infarct). All deaths occurred in the first 48 hours of reperfusion. One rat in the control group and one rat in the 4 hr-BRL group did not achieve a reduction in LDF signal to <40%; these were not included in the analysis. Thus, the final number of rats that successfully completed the experimental protocol and included in the final analysis were as follows: Saline controls n=13; Rep-BRL n=8; 2 hr-BRL n=7; 4 hr-BRL n=10; and 6 hr-BRL n=7.
Mean arterial blood pressure (MABP), partial pressure of arterial carbon dioxide (PaCO2) and oxygen (PaO2), pH and rectal temperature were within normal physiological ranges in all animals at baseline during MCAO and early reperfusion (Table 1). LDF-determined cerebral perfusion was not different in various treatment groups during MCAO (Saline: 26±3%; Rep-BRL: 29±4%; 2 hr-BRL: 28±3%; 4 hr-BRL: 30±4%; and 6 hr-BRL: 27±5%). Similarly, LDF was promptly restored on withdrawal of intraluminal suture during reperfusion in all treatment groups.
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On day 4 of recovery, the median NDS in the Rep-BRL, 2 hr-BRL, and 4 hr-BRL groups was significantly better than in the control group (Table 2). The overall median NDS in the 4 hr-BRL group was significantly better as compared with those in controls (Table 2). TTC-determined infarct volume (% of contralateral structure; corrected for swelling) was significantly attenuated both in cortex and the CP complex in the Rep-BRL (cortex: 22±6%; CP: 38±9%), 2 hr-BRL (cortex: 21±6%; CP: 40±8%), and 4 hour-BRL (cortex: 18±5%; CP: 50±8%) groups as compared with controls (cortex: 39±5%; CP: 70±4%). However, the 6 hr-BRL treatment group demonstrated significant protection in the CP complex (46±9%), but not in the cortex (23±7%) (Figure 1).
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Effect of BRL 52537 on DA and its Metabolites in the CP Complex
In microdialysis experiments, physiological parameters and intraischemic LDF were not different in BRL 52537 versus vehicle (saline)-treated rats (data not shown). In vitro probe recovery for DA, prior to implantation of the probe, was 25±5% (n=12 probes). One rat in each group was excluded because of hematoma around the probe tract on postmortem examination of the brain. Thus, 8 animals per group were included in the final analysis. There was a 6- to 8-fold increase in DA concentrations from preischemic values within 40 minutes following MCAO in both treatment groups. These values gradually returned to preischemic baseline values at reperfusion. There were no differences in increases in DA and its metabolites DOPAC and HVA (Figure 2) in the dialysates with MCAO in saline and BRL 52537-treated rats. Infarct volume at 22 hours of reperfusion was significantly attenuated in BRL 52537 (cortex: 16±4%; CP: 19±3%) as compared with saline treated controls (cortex: 53±6%; CP: 60±5%).
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Discussion |
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This study demonstrates two important findings. First, intravenous administration of a selective KOR agonist, BRL 52537, can be delayed for at least 6 hours of reperfusion after 2 hours of MCAO in the rat and still provide neuroprotection. Secondly, BRL 52537, when given as a pretreatment, does not alter levels of DA and its metabolites in the CP complex during MCAO and up to 3 hours of reperfusion, as compared with controls.
Therapeutic Opportunity with BRL 52537
KOR agonists have been of interest as potential therapy for ischemic neuroprotection for several years. We have previously shown that BRL 52537 provides significant ischemic neuroprotection when administered either as a pretreatment or at the onset of reperfusion.6,21 The finding that BRL 52537 reduces damage from experimental stroke is consistent with findings in several previous studies. Using ligand binding, Boutin et al7 demonstrated that KOR binding sites were preserved much longer (12 to 48 hours) than the - or the µ-binding sites following focal ischemia in mice. Although functional significance of these findings remains unclear, modulation of excitatory neurotransmitter release by exogenous KOR agonists on already preserved KORs on presynaptic membranes has been postulated to be one mechanism. Preservation of binding sites does not prove a correspondingly prolonged therapeutic window; however, it is a prerequisite and thus offers the potential for delayed onset of treatment. The present study defines a prolonged therapeutic opportunity of at least 6 hours with BRL 52537. We did not administer BRL 52537 beyond 6 hours of reperfusion, and it is plausible that it affords ischemic neuroprotection beyond this time point. In our study, we used BRL 52537 hydrochloride,18,19 a water-soluble agent that is highly specific for the KOR (eg, Ki –0.24 nM; Ki µ–1560 nM), with 16 times the potency of standard KOR ligands such as U-60488. Intravenous administration did not have any significant effects on physiological parameters evaluated within our study. In addition, we have previously shown that during 22 hours of treatment with BRL 52537, there is no alteration in body temperature,21 and, furthermore, prolonged treatment (4 days) does not result in gross neuropathology or myelin injury in naive, nonischemic rats.6
KOR Agonists and Neurotransmitter Systems
Several experimental studies have reported that ischemia-evoked DA release and metabolism may underlie the selective vulnerability of striatal neurons to ischemic insult.12–15 For example, depletion of catecholamine stores by 
-methyl-para-tyrosine or by surgically lesioning the nigrostriatal tract, protects intrinsic striatal neurons from injury following global cerebral ischemia.15 While the precise mechanism of neuronal injury by DA is unclear, byproducts of its metabolism such as hydrogen peroxide, superoxide ion, and oxygen radicals have been implicated in this deleterious process.23 In our study, there was an expected acute large increase in DA in the first 40 minutes microdialysis samples following the onset of MCAO. However, pretreatment with BRL 52537 did not attenuate DA levels as compared with saline-treated controls. Furthermore, we did not observe a secondary increase in DA levels for up 3 hours of reperfusion. Metabolism of DA proceeds predominantly via cytosolic neuronal reuptake and subsequent conversion to DOPAC (by monoamine oxidase), and then to HVA by the membrane-bound catechol-O-methyltransferase.24 DOPAC and HVA were decreased during MCAO in the 2 treatment groups in our study, whereas values were stable in previously published surgical sham controls.20 This is consistent with previous reports suggesting that ischemia-evoked DA accumulation is not rapidly metabolized, presumably because of impaired DA reuptake mechanisms, ischemia-induced metabolic enzyme failure, or membrane potential-dependent active transport failure.24 However, previous studies have demonstrated increased tissue levels of DOPAC and HVA for up to 8 hours following experimental stroke.15 Thus, reduced extracellular levels of DOPAC and HVA during ischemia suggest that these metabolites may be formed intracellularly with restricted amounts entering the extracellular compartment.12,24 Striatal DOPAC levels tended to be higher in controls compared with BRL 52537–treated animals throughout the course of the experiment. This nonsignificant effect is probably unrelated to drug treatment because the effect was apparent at baseline before drug treatment. During reperfusion there was a gradual but partial return of DOPAC and HVA to preischemic baseline values in both treatment groups, suggesting a recovery of reuptake and enzymatic function. We chose to monitor DA levels in the striatum because of its high DA content and the demonstrated robust ischemic neuroprotection in this region in our model. However, it is plausible that we were unable to detect attenuation of DA levels because our microdialysis sampling was from the ischemic "core," and that differences with BRL treatment existed in "penumbral" regions.
Data from several previous studies support that other antiexcitotoxic mechanisms may be important in the neuroprotection provided by KOR agonists in cerebral ischemia. For example, in vitro studies demonstrate that KOR agonists modulate glutamate toxicity by inhibiting presynaptic glutamate release, possibly by closing N-type Ca++ channels and inhibiting excitatory postsynaptic potentials by attenuating presynaptic Ca2+ influx.8 Mackay et al1 demonstrated attenuation of glutamate release with graded ischemia in experimental stroke with the KOR agonist, CI-977 (enadoline). Attenuation of ischemia-evoked NO production by BRL 52537 and the consequent reduction in early NO toxicity may represent one mechanism for this KOR agonist’s action in ischemic stroke.6 Accentuation of other inhibitory neurotransmitters by KOR agonists (eg, 
-aminobutyric acid) may represent another neuroprotective mechanism.25
In conclusion, these data demonstrate that a continuous intravenous infusion of the potent KOR agonist BRL 5253 attenuates stroke damage when given up to 6 hours following the onset of reperfusion, but not by a mechanism involving reduction in ischemia-evoked DA release. This prolonged therapeutic opportunity (8 hours from the onset of MCAO) is greater than commonly seen with other neurotransmitter modulators and offers the possibility for providing a benefit in clinical stroke treatment.
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Acknowledgments |
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We thank Ellen Gordes for her technical help with HPLC experiments. 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 an Established Investigator Grant from the American Heart Association.
Received December 19, 2003; accepted January 16, 2004.
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