(Stroke. 1997;28:198-205.)
© 1997 American Heart Association, Inc.
Articles |
Parallel Antioxidant and Antiexcitotoxic Therapy Improves Outcome After Incomplete Global Cerebral Ischemia in Dogs
the Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institute, Baltimore, Md.
Correspondence to Dr Mark Helfaer, Department of Anesthesiology/Critical Care Medicine, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287-4963.
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Abstract |
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Background and Purpose We have previously shown that incomplete global cerebral ischemia complicated by dense acidosis produces a profound secondary deterioration of energy metabolism and cerebral blood flow. Antioxidant treatment only partially averts this deterioration, suggesting that parallel or sequential mechanisms are involved in cerebral ischemic injury. We tested the hypothesis that a novel competitive N-methyl-D-aspartate (NMDA) receptor antagonist GPI 3000 (GPI) ameliorates metabolic injury and that the effectiveness of the iron-chelator and antioxidant deferoxamine (DFO) is augmented by combined therapy with GPI after incomplete global cerebral ischemia.
Methods Anesthetized dogs were treated with 30 minutes of global incomplete cerebral ischemia. Preischemic plasma glucose was raised to approximately 500 mg/dL to exaggerate lactic acidosis. Brain ATP, phosphocreatine, and pHi were measured by 31P MR spectroscopy for 180 minutes of reperfusion. Neurophysiological outcomes were assessed by evoked potential monitoring. Five groups were treated with either saline; 75 mg/kg DFO preischemia plus 75 mg/kg at reperfusion onset, followed by 27.5 mg/kg per hour for the remainder of reperfusion (DFO group); 25 mg/kg GPI pretreatment, followed by 5 mg/kg per hour (GPI-pre group); 25 mg/kg GPI at reperfusion, followed by 5 mg/kg per hour (GPI-post group); or DFO and GPI-pre at the same doses (Combined group).
Results Ischemic cerebral blood flow (microspheres: 5 to 8 mL/min per 100 g) was similar among the groups. End-ischemic pHi was also similar: 5.9 in saline, 6.1 in DFO, 6.2 in GPI-pre, 6.2 in Combined, and 6.1 in GPI-post groups. Progressive hypoperfusion was observed in all groups except Combined during reperfusion. Metabolic recovery was improved relative to saline in all drug-treated groups. Phosphocreatine recovery was improved in Combined compared with DFO and GPI-pre groups. Somatosensory evoked potential recovery was not observed in the saline group and incomplete in all treatment groups. At 60 and 90 minutes of reperfusion, DFO, GPI-pre, and Combined groups demonstrated improved recovery relative to the saline group.
Conclusions Pretreatment and posttreatment with GPI ameliorated postischemic metabolic failure, suggesting that NMDA-mediated mechanisms are more important in global cerebral ischemia complicated by dense acidosis than early studies indicated. Combined treatment with GPI and DFO improved cerebral blood flow during reperfusion and one indicator of energy recovery. These data support the hypothesis that parallel therapy aimed at antioxidant and antiexcitotoxic mechanisms of ischemic brain injury augment recovery compared with the individual agents.
Key Words: acidosis • cerebral ischemia • deferoxamine • N-methyl-D-aspartate • oxidants • spectroscopy, nuclear magnetic resonance
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction |
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Cerebral ischemia produces inadequate delivery of oxygen and substrate to brain tissue, resulting in energy failure and a complex cascade of events that may quickly lead to cell death. The precise etiology has yet to be elucidated, but multiple mechanisms acting in serial or parallel fashion are likely. Production of oxygen-derived radicals during cerebral ischemia leads to microvascular1 2 and neuronal3 injury. Oxygen-derived free radical scavengers such as superoxide dismutase are neuroprotective in focal ischemia models4 5 as well as global models of ischemia.6 Cerebral ischemia associated with lactic acidosis leads to release of free iron, which catalyzes the production of oxygen-derived free radicalsduring reperfusion by Fenton chemistry.7 We have previously shown that treatment with DFO reduces early metabolic failure secondary to global incomplete ischemia complicated by hyperglycemic acidosis.8 Similarly, the 21-aminosteroid tirilazad attenuates cerebral edema and improves SEP recovery after incomplete ischemia.9 However, recovery was incomplete with both these agents, suggesting that oxygen-derived free radical injury is only one of the mechanisms involved in cerebral ischemic injury.
Excessive release of glutamate, with consequent overstimulation of glutamate receptors and elevation of intracellular cations, is also thought to be an important mechanism in brain injury.10 11 Excitotoxicity has been implicated in neuronal injury during focal ischemia.12 13 Treatment of focal ischemia with a noncompetitive NMDA receptor antagonist such as MK-801 can reduce neuronal injury, albeit with significant adverse effects.14 15 Although non-NMDA receptor antagonists have been evaluated in models of global cerebral ischemia,16 the role of NMDA receptor antagonism in the setting of global cerebral ischemia is not well studied. Competitive NMDA receptor antagonists are effective in animal stroke models, without the undesirable adverse effects of noncompetitive antagonists.17 18 GPI 3000 (GPI), formerly known as NPC 17742 (2R,4R,5S-[2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid]), is a specific competitive NMDA antagonist19 that reduces infarction volume after transient focal ischemia.20 We hypothesized that glutamate also plays a significant role after global cerebral ischemia and that postischemic outcomes can be improved by administration of a competitive NMDA receptor antagonist either before or after ischemia.
Therefore, the purposes of the present study were (1) to determine whether NMDA receptor–mediated glutamate injury plays a role in incomplete global ischemia associated with dense acidosis and (2) to test whether parallel therapies directed at antioxidant and antiexcitotoxic mechanisms would augment recovery.
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Materials and Methods |
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This study is in compliance with the guidelines of the National Institutes of Health for care and handling of animals and was approved by our institutional animal care and use committee. The methods have been previously described in detail.21 22 23 Forty male dogs (weight, 9 to 13 kg) were anesthetized with fentanyl (50 µg/kg) and pentobarbital (6 mg/kg bolus followed by 3 mg/kg per hour). Paralysis was obtained with pancuronium bromide after adequate anesthesia, and the dogs were intubated and mechanically ventilated with supplemental oxygen to maintain arterial pH, PO2, and PCO2 in the physiological range. End-tidal CO2 concentration was monitored continuously. Arterial and venous catheters were placed for blood pressure measurements, blood withdrawal, and fluid and drug administration. A left ventricular catheter was placed for microsphere injection. The temporalis muscle was retracted from the skull, and a catheter was placed in the superior sagittal sinus through a burr hole for blood sampling. A silicone elastomer catheter was placed through a second burr hole into the left lateral ventricle for infusion of artificial cerebrospinal fluid. A temperature monitor was placed in the left parietal epidural space, and body temperature was maintained with insulation and heating blankets. An electrode was secured with dental acrylic over the right somatosensory cortex for measurement of SEPs after left forelimb stimulation.
Blood gas determination of pH, PCO2, and PO2 was performed with a Radiometer ABL electrode system. Oxygen content was analyzed with a hemoximeter (Radiometer OSM 3). Arterial blood pressure and intracranial pressure were measured with Statham transducers. CBF was measured by the radiolabeled microsphere technique (New England Nuclear Products), as previously described,8 24 at six time points: baseline before drug infusion, the midpoint of ischemia, and at 8, 30, 90, and 180 minutes of reperfusion. Animals with CBF less than 1 or greater than 12 mL/min per 100 g during ischemia were excluded from the study.
31P MRS data were obtained with the use of a Vivospec spectrometer (Otsuka Electronics) with a 1.89-T horizontal superconducting magnet (25-cm bore, Oxford Instruments) and a 5-cm-diameter surface coil, as previously described.8 An external standard (dimethyl[2-oxopropyl]-phosphonate) placed over the coil served as a marker for the spectral position when the phosphocreatine peak disappeared. Spectral areas for ATP and phosphocreatine were analyzed by planimetry and expressed as a percentage of the preischemic control for each animal. pHi was calculated as 6.77+log[(
-3.29)/(5.68-)], where is the chemical shift (in parts per million) of Pi relative to phosphocreatine.25 The precision of pHi measurements was approximately 0.06 to 0.10 units in the vicinity of pKa for Pi of 6.75 and 0.1 to 0.2 pH units in the pHi range of 5.0 to 6.0. We estimated [HCO3-]i from the Henderson-Hasselbalch equation using the MRS-derived pHi and the sagittal sinus partial pressure of CO2 as an estimate of mean tissue PCO2.21 22 Spectra were analyzed in 15-minute epochs (240 free-induction decays) in duplicate before ischemia, in three 5-minute epochs during drug infusion, in a 6-minute epoch followed by three 8-minute epochs during ischemia, in four 5-minute epochs during the first 20 minutes of reperfusion, and in 15-minute epochs for the remainder of the reperfusion period. Sagittal sinus PCO2 was measured at the midpoint of each MRS spectra.
SEPs were generated with foreleg stimulation at a rate of 5.9 per second and recorded from the skull electrode placed near the somatosensory cortex with a reference needle electrode in the snout. Signal averaging of 128 responses was performed with the Med-80 (Nicolet Instrument Corp), and replicate waves were recorded to ensure reproducibility.21 Amplitude of the primary cortical wave was measured from the first positive wave to the peak of the first negative wave at baseline, after the preischemic drug infusion, and at 60, 90, and 180 minutes of reperfusion. The SEPs are presented as percentage of the amplitude obtained before ischemia and after drug infusion.
Serum glucose was raised to approximately 500 mg/dL at the onset of ischemic cerebral injury and maintained throughout ischemia. Global incomplete cerebral ischemia was produced by infusion of artificial cerebrospinal fluid from a 38°C pressurized reservoir through a line in a water jacket and into the lateral ventricle catheter. Intracranial pressure was elevated to produce a cerebral perfusion pressure of 10 mm Hg, while mean arterial pressure was allowed to change spontaneously. After 30 minutes of ischemia, the fluid reservoir was disconnected to allow cerebrospinal fluid to drain, and intracranial pressure rapidly decreased toward baseline. This procedure reliably produces a constant CBF within the desired range of 1 to 12 mL/min per 100 g throughout the ischemic period.21 At the end of 3 hours of reperfusion, the animals were killed with an intravenous bolus of potassium chloride.
Dogs were randomized into five groups, with eight animals in each group. The control group received normal saline before ischemia in an amount equivalent to the diluent volume of drug in the treated groups. Dogs in the DFO group received a 75-mg/kg bolus over 15 minutes before ischemia, a second 75-mg/kg bolus at 28 minutes of ischemia, and 27.5 mg/kg per hour for the reperfusion period. A third group (GPI-pre) received GPI as a 25-mg/kg bolus before ischemia and 5 mg/kg per hour starting 28 minutes into ischemia and continuing throughout the reperfusion period. Animals receiving both drugs (Combined group) were given the DFO and GPI-pre regimens. A final group (GPI-post) was given a 25-mg/kg bolus of GPI at 28 minutes of ischemia, followed by 5 mg/kg per hour throughout reperfusion. The dose of GPI was chosen from pilot data, which showed a maximum reduction of SEPs of less than 20% without reduction of CBF. We used a large dose of DFO, based on results of our previous studies.8
All data are presented as mean±SEM, and the significance level was set at P=.05 for all comparisons. Data were analyzed with the use of a two-way ANOVA with drug treatment analyzed between subjects and time within subjects. If differences were identified, then one-way ANOVA with the Newman-Keuls test was used to distinguish significant group differences at specific time points or to compare differences from baseline values within groups. To evaluate the parallel therapy hypothesis, differences among the DFO, GPI-pre, and GPI-post groups were evaluated with this same approach. Because the SEP data were not normally distributed, a nonparametric Kruskal-Wallis test was used to determine recovery differences.
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Results |
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Physiological variables were controlled throughout the experimental protocol. There were no differences between groups at any time point in arterial blood gas values, including pH, PCO2, PO2, O2 saturation, or glucose (Table
). Similarly, there were no significant differences in epidural temperature between groups at any time point. Mean arterial pressure rose during ischemia and returned to baseline levels during reperfusion in all animals. Intracranial pressure fell to equivalent levels at onset of reperfusion. All groups experienced a secondary rise, which was less prominent in the Combined group (Table). There were no significant differences in cerebral perfusion pressure between groups at any time point.
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Baseline forebrain blood flows were equivalent in all groups. During ischemia, CBF fell in all groups to 8±1 in control, 8±2 in DFO, 6±1 in GPI-pre, 5±1 in Combined, and 8±1 mL/min per 100 g in GPI-post groups. There was an equivalent hyperemic response at 8 minutes of reperfusion (Fig 1), followed by a progressive hypoperfusion in all groups except the Combined group. CBF at 180 minutes was below baseline in all groups except the Combined group.
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Consistent with our previous work with this model, both pHi (Fig 2) and [HCO3-]i fell severely by end-ischemia. There were no overall differences in pHi between groups during ischemia. However, pHi was lower in the saline than the Combined group at 19 minutes of ischemia and lower than the Combined and GPI-pre groups at 27 minutes of ischemia. By 45 minutes of reperfusion, pHi was improved in all groups compared with the saline group, but recovery was incomplete in all groups. [HCO3-]i fell to 1 to 2 mmol/L at end-ischemia in all groups. Recovery was incomplete in all groups, and at 180 minutes only Combined had improved recovery relative to the saline group.
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Reduction of phosphocreatine and ATP during ischemia was equivalent in all groups (Fig 3); ATP was higher in the Combined relative to the saline group only at the 27-minute time point. In the saline group, recovery of phosphocreatine and ATP was minimal in all animals. In contrast, all drug treatment groups experienced high-energy phosphate recovery during the 180 minutes of reperfusion. In the Combined group, phosphocreatine recovered to baseline values by 30 minutes of reperfusion, and recovery was greater relative to the other treatment groups at 90 to 180 minutes of reperfusion. All groups showed significant recovery of ATP by 75 minutes of reperfusion, but there were no overall differences among the drug treatment groups.
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The SEPs did not reappear after ischemia in saline-treated animals and recovered incompletely in all other groups. Two animals in the GPI-post group demonstrated a small recovery, but this was not statistically different from the saline group. In DFO, GPI-pre, and Combined treatment groups, SEP recovery was improved relative to control at 60 and 90 minutes of reperfusion but not at 180 minutes (Fig 4).
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Discussion |
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This study demonstrates two major findings. First, these data support the hypothesis that NMDA-mediated excitotoxicity is an important mechanism of brain injury after global ischemia accompanied by dense acidosis. Interestingly, both pretreatment and posttreatment with GPI ameliorate secondary metabolic deterioration during reperfusion. Second, parallel therapy with antioxidant and antiexcitotoxic agents also ameliorates metabolic deterioration, as measured by the steady state restoration of phosphocreatine, which was best with combined therapy. In addition, CBF recovered to a greater degree with parallel therapy than with single-agent treatment.
We have previously shown that treatment with DFO ameliorates metabolic failure.8 Iron-catalyzed oxygen radical production and subsequent peroxidative damage to lipids and protein oxidation may be important mechanisms in ischemic brain injury, particularly when the acidosis is severe. In our model of hyperglycemic incomplete ischemia, free iron increases in many brain regions during early reperfusion, potentially amplifying radical production rate.26 Iron catalysis of tyrosine nitration by peroxynitrite may also be an important mechanism and does not depend on the prior reduction of iron to the ferrous state.27
Numerous studies have shown increases in extracellular glutamate concentrations after episodes of cerebral ischemia.28 29 30 The mechanism(s) of glutamate-induced neurotoxicity is not fully clear but likely involves an influx of sodium and calcium into cells, with subsequent initiation of a cascade of events resulting in cell death.31 Neurotoxic mechanisms may also include glutamate-induced nitric oxide elaboration32 and production of radical species such as peroxynitrite.33 34 Glutamate toxicity in the present study may be related to the profound depletion of high-energy phosphates that occurs by end-ischemia; a threshold relationship has been shown in MRS and non-MRS studies.35 36 37 Depletion of high-energy phosphates likely produces neuronal depolarization as ATP-dependent ionic pumps fail and extracellular potassium concentration rises. ATP-dependent reuptake mechanisms may contribute to glutamate-induced brain injury as well.
We determined the efficacy of the NMDA receptor antagonist GPI administered both before ischemia and at the onset of reperfusion and showed that GPI ameliorates metabolic failure in both groups. This finding was surprising because of the profound fall in pHi observed during ischemia in all animals. Experimental evidence indicates that glutamate receptors can be inactivated by extreme acidosis, at least in vitro.38 Gifford et al39 reported that reduced extracellular pH depresses NMDA receptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation injury in cortical neuronal cultures. In subsequent studies, the combination of extracellular acidosis and glutamate receptor antagonism provided greater neuronal protection than glutamate receptor antagonism alone.38 Neuronal protection through acidosis-mediated mechanisms may be related to the duration and severity of the acidosis, since protection is lost as the duration of acidosis is extended or if the fall in pH is severe.38 40 41 Once acidosis begins to resolve during reperfusion, it is likely that glutamate receptors and associated downstream ion fluxes could again become active. Therefore, the severity of ischemic acidosis and slow restoration of tissue pH during reperfusion in the present model may explain why postischemic outcomes were improved in both the GPI-pre and GPI-post groups.
Although many agents have been shown to provide partial neuroprotection, no single agent provides complete protection within the complexity of ischemic brain injury. Therefore, we anticipated that blocking two potentially important mechanistic pathways could amplify acute postischemic recovery. Parallel pretreatment with GPI and DFO improved CBF and, less strikingly, energy phosphate recovery relative to individual treatment. Restoration of phosphocreatine was amplified in combined therapy by 90 minutes of reperfusion. All treatments equally improved overall ATP recovery, salvaging the tissue from the progressive metabolic death observed in saline-treated animals. These pathways may act in parallel, sequentially, or both, and our present data do not distinguish the precise interaction between NMDA and oxygen radical–mediated cytotoxicity. Both NMDA and non-NMDA receptor antagonism may lead to a decreased production of free radicals and lead to less tissue damage.32 33 34 DFO may then further limit the production of free radicals through inhibition of iron-dependent production of radicals. DFO and GPI may also act in parallel mechanisms to ameliorate metabolic deterioration. This may explain why DFO and GPI appear to have additive and likely parallel mechanistic effects on improving most physiological parameters, with the possible exception of the preservation of CBF, which may represent a synergistic and sequential mechanistic effect.
The observation that CBF recovered to baseline values only in the combined group cannot be explained by differential forebrain blood flow during ischemia. Intraischemic blood flow was equivalent in all groups. Similarly, differences in intraischemic acidosis cannot account for the lack of hypoperfusion observed in the Combined group. There were no overall differences in the reduction of pHi during ischemia, although pHi was statistically higher at one time point in the Combined and GPI-pre groups than in the saline-treated group. However, recovery was equivalent in the GPI-pre and GPI-post groups, suggesting that other factors are important in the efficacy of GPI than decreased severity of intraischemic acidosis. Augmented CBF recovery with the combined antioxidant and NMDA receptor antagonist treatment could simply reflect the presence of an increased proportion of metabolically active cells, both neuronal and nonneuronal. Because NMDA receptors are not likely present in cerebral microvessels42 and isolated vessels from several species fail to respond to NMDA or glutamate,43 it seems unlikely that a treatment overlap directly preserved perfusion in the Combined animals.
There was only modest recovery of SEPs in any treatment group, which is explained by the severity of the ischemic insult. There was no recovery of SEPs in the GPI-post group, which could suggest that excitatory amino acid–mediated mechanisms of neuronal injury are more important during ischemia than reperfusion. Alternatively, the lack of recovery could be related to the 3-hour window of observation, and we cannot exclude the possibility of delayed SEP recovery. Intravenous GPI administration at the present dose rapidly reduces SEP amplitude by as much as 30% of baseline values. Posttreatment with this agent could slow the reemergence of the evoked potential waveform, independent of postischemic events.
In conclusion, treatment with the specific competitive NMDA receptor antagonist GPI ameliorates early metabolic failure after incomplete global ischemia complicated by exaggerated acidosis. This suggests that NMDA-mediated excitoxicity is an important component of global cerebral ischemic injury, despite the presence of severe lactic acidosis. DFO also ameliorates metabolic failure, confirming our previous findings.8 Parallel antioxidant and antiexcitotoxic therapy improves hemodynamic and metabolic, but not electrophysiological, recovery relative to single agents. These data support the hypothesis that parallel therapy aimed at two different mechanisms of ischemic brain injury can augment recovery compared with single-mechanism approaches. These data represent only short-term physiological improvement, which motivates further investigations utilizing more long-term outcome measures such as behavioral, neurological, and neurohistological outcomes to evaluate the ultimate effect of these agents in the setting of cerebral injury.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grants from the National Institutes of Health (NR-03521, NS-33668). We would like to thank Judy Klaus for outstanding technical support. We would also like to thank Guilford Pharmaceuticals, Baltimore, Md, for the generous gift of GPI 3000.
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Footnotes |
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Drs Hurn and Traystman hold a patent pending for the use of GPI 3000 in cardiac arrest. The terms of this arrangement have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies.
Received June 26, 1996; revision received September 18, 1996; accepted October 7, 1996.
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Editorial Comment
Departments of Neurological Surgery and NeurologyUniversity of CaliforniaSan Francisco, Calif
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