(Stroke. 1995;26:688-695.)
© 1995 American Heart Association, Inc.
Articles |
Deferoxamine Reduces Early Metabolic Failure Associated With Severe Cerebral Ischemic Acidosis in Dogs
From the Department of Anesthesiology/Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Md.
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Abstract |
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Background and Purpose Postischemic metabolic injury may be mediated by acidosis and tissue bicarbonate depletion, with consequent iron mobilization and oxygen radical formation during reperfusion. We have previously shown that reducing intracellular pH to below 5.7 and bicarbonate ion to below 1 to 2 mmol/L during hyperglycemic ischemia produces a profound secondary deterioration of brain ATP and cerebral blood flow during reperfusion. This study tested the hypothesis that pretreatment with free deferoxamine ameliorates metabolic decay and delayed hypoperfusion after global hyperglycemic ischemia. In addition, deferoxamine conjugated to a high-molecular-weight starch was administered to determine the importance of an intravascular site of action. Iron-loaded deferoxamine was used to determine whether the iron chelation properties of deferoxamine are important to postischemic viability as distinguished from the agent's significant radical scavenging potential.
Methods Cerebral ATP, phosphocreatine, and pH were measured by 31P magnetic resonance spectroscopy in anesthetized dogs. Tissue bicarbonate concentration was calculated from the Henderson-Hasselbalch equation. Incomplete cerebral ischemia was produced by intracranial pressure elevation for 30 minutes with plasma glucose at 540±15 mg/dL. Free deferoxamine, saline vehicle, hydroxyethyl starch–conjugated deferoxamine, hydroxyethyl starch vehicle, and deferoxamine loaded with equimolar ferric chloride were administered intravenously in five groups of dogs. The dose of deferoxamine was 50 mg/kg before ischemia, 50 mg/kg at the onset of reperfusion, and 50 mg/kg over the 180-minute reperfusion period.
Results Ischemic hemispheric blood flow (mean, 6 to 8 mL/min per 100 g), intracellular pH (5.7 to 6.0), and bicarbonate levels (1 to 2 mmol/L) were similar in all groups. During reperfusion, cerebral pH and bicarbonate recovered only in the free-deferoxamine group. Both ATP and phosphocreatine initially increased in all groups, but recovery was sustained only in the free-deferoxamine group. Secondary losses of energy phosphates and cerebral oxygen consumption were observed in all other groups, accompanied by progressive reduction of perfusion.
Conclusions These data support the hypothesis that iron-catalyzed oxygen radical production plays an important role in acidosis-mediated mechanisms of ischemic brain injury. The results with free and iron-loaded deferoxamine suggest that iron scavenging is an important, but not necessarily the principal, component of this mechanism. The poor recovery seen with conjugated deferoxamine indicates that the beneficial action of deferoxamine is not localized within the intravascular compartment.
Key Words: acidosis • cerebral ischemia • iron • spectroscopy, nuclear magnetic resonance • dogs
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Introduction |
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Severe acidosis enhances histological and metabolic brain injury after global cerebral ischemia1 ; however, the central mechanism(s) for pH-mediated damage is unknown. We have shown previously that reducing intracellular pH (pHi) to below 5.7 and bicarbonate ion [HCO3-]i to below 1 to 2 mmol/L during hyperglycemic global ischemia produces a profound secondary decay of brain ATP and cerebral blood flow (CBF) during reperfusion.2 Furthermore, the secondary decay does not occur during early reperfusion after hypercapnic ischemia when the fall in [HCO3-]i, but not pHi, is attenuated.3 Lactic acid but not carbon dioxide amplifies lipid peroxidation in brain homogenates, and this amplification is inhibited by the iron chelator deferoxamine.4 Rehncrona et al4 hypothesized that ischemic lactic acidosis increases iron dissociation from carrier proteins that use carbonate binding (eg, transferrin5 ), whereas carbonic acidosis acts to stabilize [HCO3-] and carbonate-bound iron. Iron mobilized by lactic acidosis in vivo would be expected to cause increased oxygen radical production during reperfusion via Fenton chemistry.4
We investigated whether the in vivo metabolic failure observed after hyperglycemic ischemia and consequent brain bicarbonate titration are mediated by such a mechanism. The first aim of the present study was to determine if pretreatment with deferoxamine ameliorated metabolic and CBF deficits after global ischemia accompanied by exogenous glucose elevation. Second, a high-molecular-weight conjugate of deferoxamine with poor blood-brain barrier permeability was used to determine the importance of an intravascular site of iron catalysis. The hydroxyethyl starch–conjugated chelator is equipotent to free deferoxamine but has a prolonged intravascular retention time.6 7 Last, iron-loaded deferoxamine was used to determine potential radical scavenging effects (eg, that of peroxyl radicals8 ) unrelated to iron chelation.
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Materials and Methods |
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This study was approved by the institutional animal care and use committee and is in compliance with the guidelines of the National Institutes of Health for care and handling of animals. The methods have been described in detail.2 3 Male dogs (7 to 10 kg) were anesthetized with intravenous fentanyl (50 µg/kg) and pentobarbital (6 mg/kg, then 3 mg/kg per hour) and mechanically ventilated with supplemental oxygen. Muscle paralysis was achieved with pancuronium bromide (0.1 mg/kg). Systemic arterial and venous catheters were placed for pressure and microsphere measurements and for infusion of fluids and drugs. Temporalis muscles were fully retracted from the skull, and a superior sagittal sinus catheter was placed through a midline skull burr hole near the junction of the coronal sutures. The left lateral ventricle was cannulated through a second burr hole with a Silastic ventricular drain catheter (Cordis) for infusion of mock cerebrospinal fluid and measurement of intracranial pressure (ICP). An epidural thermistor was inserted through an additional burr hole for continuous monitoring of brain temperature. An electrode for measuring the somatosensory evoked potential (SEP) was secured with dental acrylic into a burr hole contralateral to the ventricular catheter. Primary cortical wave amplitude in response to forelimb stimulation was measured. Animals were placed in a cradle equipped with a warm water blanket and fiberglass insulation to maintain normothermic epidural temperature.
Arterial and sagittal sinus blood samples were analyzed for PO2, PCO2, and pH levels with a Radiometer ABL electrode system. Oxygen content was measured with a CO-Oximeter (No. 282, Instrumentation Laboratories). Arterial blood pressure and ICP were measured with Statham transducers. Blood flow was measured by the radiolabeled-microsphere technique with microspheres 16±0.5 µm in diameter (Dupont-New England Nuclear Products) as previously described.2 Cerebral O2 uptake (CMRO2) was calculated by multiplying the arteriosagittal sinus O2 content difference by blood flow to the cerebral hemispheres.
31P magnetic resonance spectra were obtained using 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.2 3 Spectral
areas for ß-ATP, phosphocreatine, and inorganic phosphate were
analyzed by planimetry and expressed as a percentage of the respective
area in the control spectra for each animal. Intracellular pH was
determined by methods previously described by Petroff et
al,9 using constants derived from our titration data:
pHi=6.73+log[(
-3.07)/(5.68-)] where is the
chemical shift of inorganic phosphate relative to phosphocreatine. An
external standard (dimethyl [2-oxopropyl]-phosphonate) placed over
the coil served as a marker for the spectral position when the
phosphocreatine peak disappeared. Intracellular
[HCO3-] was calculated from the
Henderson-Hasselbalch equation using a pKa of 6.12,
pHi as measured by magnetic resonance spectroscopy (MRS),
and sagittal sinus PCO2 with a solubility
coefficient of 0.0314 mmol/L per millimeter of mercury. Changes in
sagittal sinus PCO2 were assumed to
approximate changes in tissue PCO2.
After baseline measurements were made, drug or vehicle was administered intravenously over 15 minutes. An intravenous solution of 50% dextrose was then infused to maintain plasma glucose at approximately 400 to 500 mg/dL. Global incomplete ischemia was produced by infusion of warmed cerebrospinal fluid from a heated reservoir system into the lateral ventricular catheter. ICP was maintained at 10 to 15 mm Hg below mean arterial pressure, while arterial pressure spontaneously changed. This procedure produces a relatively constant CBF over the 30-minute ischemic period.2 At the end of ischemia, the glucose infusion was discontinued. The fluid reservoir was disconnected, and ICP rapidly decreased toward baseline values. After 3 hours of reperfusion, the anesthetized dogs were killed with intraventricular potassium chloride injection. MRS spectra were analyzed in 15-minute epochs in duplicate before ischemia, in three 5-minute epochs during treatment, in one 6-minute and 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 reperfusion. Sagittal sinus PCO2 and SEP were measured at the midpoint of each MRS spectrum. CBF and CMRO2 were measured at baseline, at 18 minutes of ischemia, and at 8, 30, 90, and 180 minutes of reperfusion.
Experimental groups were as follows: (1) free deferoxamine (DFO, n=8, Sigma), receiving 50 mg/kg in 50 mL saline immediately before ischemia, 50 mg/kg in 50 mL at the onset of reperfusion, and 50 mg/kg in 50 mL over the remainder of the reperfusion period; (2) saline vehicle (n=8) receiving the same volume as the DFO group over the same time frame; (3) high-molecular-weight hydroxyethyl starch–conjugated (10 g%) deferoxamine (HES-DFO, n=5, Biomedical Frontiers), receiving 50 DFO Eq/kg in 33 mL immediately before ischemia, 50 DFO Eq/kg in 33 mL at reperfusion onset, and 50 DFO Eq/kg in 33 mL over the remainder of reperfusion; and (4) hydroxyethyl starch vehicle (10 g% starch in physiological saline) (HES, n=6, Biomedical Frontiers) receiving the same volume as the HES-DFO group over the same time frame. An additional group of animals (Fe-DFO, n=4) was treated with deferoxamine loaded with equimolar ferric chloride in the same timing and dosage as the free deferoxamine group. The Fe-DFO animals were studied post hoc and not randomized with the experimental groups.
All data are presented as mean±SEM, and the significance level was set at P<.05 in all tests. Dogs with ischemic CBF values of <1 or >12 mL/min per 100 g were excluded from the analysis. Data were analyzed with a two-way ANOVA with drug treatment as the between-subject factor and time (repeated measures) as the within-subject factor. If the treatment group effect or group-time interaction was significant, then the Newman-Keuls test was used to distinguish individual groups at specific time points. To compare differences with baseline values, a post hoc Dunnett's test was applied if the time effect was significant.
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Results |
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Arterial blood gas levels and epidural temperature were controlled during the experimental protocol; therefore, there were no differences in these values among groups (Table
). Epidural
temperature remained at normothermic levels during ischemia and
reperfusion.
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During ischemia, mean arterial pressure rose transiently in all groups
as ICP was elevated and then remained unchanged during reperfusion (Fig 1). A secondary increase in ICP during reperfusion was
observed in all animals but was less prominent in the DFO-treated
group. During ischemia, CBF was reduced equivalently in all groups
(saline, 7±1; DFO, 8±1; HES, 8±1; and HES-DFO, 5±1 mL/min per 100
g). During reperfusion, a progressive hypoperfusion was evident in the
saline, HES, and HES-DFO groups but not in the DFO group (Fig 2). In the DFO group, CBF remained at baseline levels at
180 minutes of reperfusion. CMRO2 was severely reduced
during ischemia and did not regain baseline levels during
reperfusion in any group (Fig 2). However, recovery levels were higher
in the DFO group relative to the saline group by 180 minutes of
reperfusion.
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As expected, normothermic incomplete ischemia coupled with elevated
intraischemic plasma glucose produced a large fall in pHi
and [HCO3-]i (Fig 3). Equivalent reductions in pHi were
achieved by the end of ischemia in all groups (saline, 5.88±0.04; DFO,
5.99± 0.10; HES, 5.67±0.10; and HES-DFO, 5.84±0.08), and
[HCO3-]i was uniformly reduced
to 1 to 2 mmol/L. During reperfusion, pHi and
[HCO3-]i recovered in the DFO
group only. Both phosphocreatine and ATP were severely reduced over the
30 minutes of ischemia, and a similar loss of both energy phosphates
occurred in all treatment groups (Fig 4). On
reperfusion, phosphocreatine and ATP initially increased in all groups,
but recovery was sustained only in the DFO group. In the vehicle and
HES-DFO animals, phosphocreatine and ATP decreased to undetectable
levels by 180 minutes.
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Initial SEP amplitude was not different among groups (saline, 72±20; DFO, 61±9; HES, 84±13; and HES-DFO, 45±13 µV). Recovery of an SEP waveform was absent or minimal during the 3 hours of reperfusion in all animals, regardless of treatment. At 180 minutes, 2 of 8 DFO animals exhibited an SEP waveform (12% and 16% of baseline amplitude), as did 2 of 6 HES animals (5% and 7% of baseline amplitude). The SEP remained isoelectric in all dogs in the saline and HES-DFO groups.
Recovery in the Fe-DFO animals paralleled that in the groups treated
with saline, HES, and HES-DFO. In the Fe-DFO group, arterial blood
pressure was unchanged by administration of iron-loaded deferoxamine
and remained at baseline values throughout reperfusion. ICP initially
recovered and then began to steadily increase by 30 minutes of
reperfusion. Plasma glucose was elevated during ischemia to values
similar to those in the other experimental groups (534±16 mg/dL during
ischemia). CBF fell to 9±2 mL/min per 100 g (range, 4 to 12 mL/min per
100 g) during ischemia, initially recovered (122±16 mL/min per 100 g
at 8 minutes of reperfusion), then fell to 6±5 mL/min per 100 g by 180
minutes. The hypoperfusion evident at this latter time point was
significant relative to the recovery observed in the DFO group (25±14
mL/min per 100 g). Mean pHi and
[HCO3-]i during ischemia were
6.10±0.05 and 2.1± 0.2 mmol/L, respectively, and recovery was
incomplete in each animal treated with Fe-DFO. In these animals,
high-energy phosphates were reduced during ischemia in the same manner
as in the other groups; however, post-ischemic metabolic
deterioration was evident in each Fe-DFO animal by 180 minutes of
reperfusion (Fig 5).
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Discussion |
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This study demonstrates three major findings. First, deferoxamine ameliorated the metabolic and CBF deterioration that was consistently observed during reperfusion in our experimental model of incomplete global ischemia coupled with elevated intraischemic plasma glucose. Second, only the low-molecular-weight form of deferoxamine was beneficial. The form of deferoxamine with presumed poor blood-brain barrier permeability (HES-DFO) did not improve postischemic outcome. Third, iron-loaded deferoxamine was not effective in preventing postischemic metabolic and perfusion abnormalities, suggesting that the iron-scavenging properties of deferoxamine are important to its effects in this ischemic model. These data support the hypothesis that iron-catalyzed oxygen radical production is one important mechanism in ischemic brain injury, specifically when acidosis is profound and brain bicarbonate is depleted. The site of iron catalysis is not intravascular or at the plasma-endothelium interface.
The striking observation of secondary loss of high-energy phosphates and CBF deterioration in the vehicle and HES-DFO groups during reperfusion is consistent with our previous work with hyperglycemic global ischemia associated with elevated tissue lactate levels.2 3 10 Others have reported similar metabolic and hemodynamic outcomes when intraischemic acidosis is severe.11 12 13 14 However, the mechanism by which acidosis limits postischemic recovery remains in question. One potential mechanism involves iron-catalyzed oxygen radical production and consequent peroxidative damage to lipids and protein oxidation. Under physiological conditions, brain iron is largely complexed to protein carriers (ie, transferrin, lactoferrin) for intravascular and transmembrane transport.5 15 16 To cause damage through catalysis of hydroxyl radical formation, iron must be in its ionic form.17 It has been suggested that, at least in vitro, elevated lactic acid but not carbonic acid leads to proton-induced dissociation of carbonate bonds in the transferrin-iron complex, increasing the availability of pro-oxidant ionic iron.4 Our previous in vivo observation of complete ATP and CBF short-term recovery after normoglycemic ischemia coupled with high levels of arterial CO23 is consistent with the carbonate hypothesis. Hypercapnic ischemia produced pHi values at the same level as that attained during hyperglycemia in the present study but produced intraischemic [HCO3-]i of approximately 6 mmol/L. Furthermore, 31P MRS studies using this same ischemic model suggest that tirilazad, an anti–lipid peroxidation agent, enhances early metabolic recovery when [HCO3-]i is depleted during severe incomplete ischemia.9 18 These findings, as well as those from the present study showing that deferoxamine improves early metabolic and blood flow recovery even when intraischemic [HCO3-]i fell to below 1 to 2 mmol/L, support the hypothesis that severe lactic acidosis causes radical damage by an iron-mediated mechanism.
If iron is mobilized from its carrier proteins during the low-pH, low-HCO3- conditions of ischemia and early reperfusion, then free iron likely binds nonspecifically to a variety of protein and small molecular moieties or augments a low-molecular-weight, non–protein-bound tissue pool.19 Others have demonstrated an increase in low-molecular-weight iron species in brain after cardiac arrest, in conjunction with reduced indicators of lipid peroxidation after deferoxamine treatment.20 21 Regional peroxidative capacity in brain correlates with local endogenous iron content.22 Increases in pro-oxidant iron may be compartmentalized in some manner, since cerebrospinal fluid bleomycin-detectable iron does not increase after ischemia, under normoglycemic or hyperglycemic conditions.23
Deferoxamine is a known potent iron chelator that has been well studied in cerebral injury, ischemia, and cardiac arrest.17 20 24 25 26 27 Our principal goal was not to examine the therapeutic benefit of deferoxamine but rather to test a specific mechanism of injury in the hyperglycemic and severely bicarbonate-depleted brain. We used a large dose of deferoxamine, which has previously been shown to ameliorate cerebral damage associated with ischemia/reperfusion.20 25 26 Our preliminary data indicated a clear effect of deferoxamine at the dosages subsequently used in the study. The hypothesis of Rehncrona et al4 predicts iron mobilization during ischemia once tissue bicarbonate is depleted. Thus, we initiated deferoxamine treatment before ischemia to assure drug delivery to the brain before reducing blood flow. Therefore, these experiments do not distinguish the importance of iron-directed therapies in neuroprotection versus postischemic resuscitation.
In addition to its iron-chelation properties, deferoxamine has significant radical-scavenging properties via hydrogen-donating free hydroxamate groups. At millimolar concentrations, the agent can inhibit superoxide activity17 28 and stimulate cyclooxygenase activity leading to increased prostacyclin levels.29 It is unlikely at the doses used in the present study that these levels of deferoxamine were attained. However, deferoxamine at much lower concentrations inhibits hydroxyl radical formation from peroxynitrite30 ; therefore, it remains possible that deferoxamine also acted to reduce peroxynitrite toxicity. In addition, both deferoxamine and iron-loaded deferoxamine have been shown to scavenge peroxyl radicals in a model lipid peroxidation system using linoleic acid suspension.8 Nevertheless, the progressive loss of cerebral perfusion and ATP recovery, increase in ICP, and incomplete restoration of brain pH observed in the iron-loaded deferoxamine–treated animals were clearly different from the results of treatment with free deferoxamine. These comparisons strengthen the hypothesis that iron scavenging is essential to initial recovery from global ischemia exacerbated by excessive lactic acidosis.
Hydroxyethyl starch–conjugated deferoxamine has also been shown to protect in oxidant-associated reperfusion injury in heart, liver,31 and brain after cardiac arrest.32 The hydroxyethyl starch–conjugated deferoxamine formulation has an average molecular weight of 30 000 D and is equipotent to free deferoxamine6 as measured by inhibition of deoxyribose degradation.7 In addition, hydroxyethyl starch itself has been reported to scavenge hydroxyl radical.7 The poor recovery with hydroxyethyl starch–conjugated deferoxamine and the clearly beneficial effect of low-molecular-weight deferoxamine (560 D) suggest that penetration into the endothelium or parenchyma is necessary for metabolic and vascular protection. It is not known how rapidly the low-molecular-weight agent crosses into brain in vivo. Deferoxamine penetration into brain has been described at doses not dissimilar to those used in the present study.33 More recently, Palmer et al34 demonstrated rapid and substantial accumulation of deferoxamine into neonatal rat brain after subcutaneous administration. Although the large amounts of drug present in brain after systemic administration may be unique to the immature brain, these results suggest that free deferoxamine is likely to gain endothelial or parenchymal access within the time frame of the present study.
Our results focus on early metabolic and CBF recovery after prolonged global ischemia. Katsura et al35 recently reported enhancement of histological brain injury but not seizure activity 1 week after hypercapnic ischemia when compared with normocapnic, normoglycemic animals. Although [HCO3-]i was not reported, these data raise the possibility that short-term beneficial effects of hypercapnia-induced bicarbonate conservation during ischemia may not be as important to the eventual outcome as the intraischemic reduction in intracellular/extracellular pH. The contribution of iron-catalyzed radical generation under these conditions remains to be determined.
There were no differences in the levels of CBF, pHi, or [HCO3-]i during ischemia among any of the groups, indicating that treatment with deferoxamine did not alter the severity of ischemia. Recovery of energy phosphates and pH, but not the return of SEPs, was improved by deferoxamine, suggesting that restoration of neuronal ion conductance is incomplete within the imposed time frame or that deferoxamine is acting within a nonneuronal compartment. The latter possibility is consistent with the observation of limited neuronal immunostaining for transferrin or ferritin in cerebral cortex.36 However, blood flow was normalized throughout all brain regions only in the DFO group. In subcortical gray and white matter, iron and transferrin are localized with microvessel walls, as well as within perivascular oligodendrocytes.37 The source of transferrin in endothelial cells in vivo is not clear, but a role in receptor-mediated transport of iron across the blood-brain barrier and within the brain is likely.15 38 Endothelial pathology and blood flow abnormalities are heightened by hyperglycemic ischemia,12 39 40 as is the presence of perivascular superoxide anion.41 Therefore, we hypothesize that the exacerbated acidosis associated with hyperglycemia and prolonged ischemia in our experimental model precipitate iron availability at the level of the vasculature, likely within endothelium, for catalysis of radical generation and peroxidative injury.10 As a consequence, reperfusion is dominated by impaired cerebral perfusion, progressive metabolic failure, edema, and elevated ICP, leading to further impairment of perfusion.
In conclusion, free but not iron-loaded deferoxamine ameliorated early metabolic and CBF failure after global ischemia complicated by exaggerated acidosis and depletion of brain bicarbonate. In contrast, high-molecular-weight deferoxamine conjugate or hydroxyethyl starch vehicle did not alter metabolic recovery. These results suggest that the relevant site of iron chelation is not intravascular and that inhibition of iron-catalyzed radical mechanisms can preserve viability during early reperfusion.
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Acknowledgments |
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This work was supported by grants from the National Institutes of Health (NR-06730, NR-03521, NS-20020) and the Maryland Affiliate of the American Heart Association. Hydroxyethyl starch–conjugated deferoxamine and hetastarch solutions were provided as a generous gift by Biomedical Frontiers, Minneapolis, Minn. The authors thank Judy Klaus and Candy Berryman for outstanding technical and secretarial assistance, respectively.
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Footnotes |
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Reprint requests to Patricia D. Hurn, PhD, Department of Anesthesiology/Critical Care Medicine, Blalock 1404, The Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287-4961.
Received April 25, 1994; revision received November 22, 1994; accepted December 29, 1994.
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