(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.
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
This article has been cited by other articles:
 |
|
 |
|
  D. W. Lee, S. Rajagopalan, A. Siddiq, R. Gwiazda, L. Yang, M. F. Beal, R. R. Ratan, and J. K. Andersen Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity: MODEL FOR THE POTENTIAL INVOLVEMENT OF THE HYPOXIA-INDUCIBLE FACTOR PATHWAY IN PARKINSON DISEASE J. Biol. Chem., October 16, 2009; 284(42): 29065 - 29076. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Siddiq, I. A. Ayoub, J. C. Chavez, L. Aminova, S. Shah, J. C. LaManna, S. M. Patton, J. R. Connor, R. A. Cherny, I. Volitakis, et al. Hypoxia-inducible Factor Prolyl 4-Hydroxylase Inhibition: A TARGET FOR NEUROPROTECTION IN THE CENTRAL NERVOUS SYSTEM J. Biol. Chem., December 16, 2005; 280(50): 41732 - 41743. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Warner, H. Sheng, and I. Batinic-Haberle Oxidants, antioxidants and the ischemic brain J. Exp. Biol., August 15, 2004; 207(18): 3221 - 3231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Gilgun-Sherki, Z. Rosenbaum, E. Melamed, and D. Offen Antioxidant Therapy in Acute Central Nervous System Injury: Current State Pharmacol. Rev., June 1, 2002; 54(2): 271 - 284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Zaman, H. Ryu, D. Hall, K. O'Donovan, K.-I Lin, M. P. Miller, J. C. Marquis, J. M. Baraban, G. L. Semenza, and R. R. Ratan Protection from Oxidative Stress-Induced Apoptosis in Cortical Neuronal Cultures by Iron Chelators Is Associated with Enhanced DNA Binding of Hypoxia-Inducible Factor-1 and ATF-1/CREB and Increased Expression of Glycolytic Enzymes, p21waf1/cip1, and Erythropoietin J. Neurosci., November 15, 1999; 19(22): 9821 - 9830. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Demchuk, L. B. Morgenstern, D. W. Krieger, T. Linda Chi, W. Hu, T. H. Wein, R. J. Hardy, J. C. Grotta, and A. M. Buchan Serum Glucose Level and Diabetes Predict Tissue Plasminogen Activator–Related Intracerebral Hemorrhage in Acute Ischemic Stroke Stroke, January 1, 1999; 30(1): 34 - 39. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Liu, R. E. Rosenthal, Y. Haywood, M. Miljkovic-Lolic, J. Y. Vanderhoek, G. Fiskum, and R. J. Traystman Normoxic Ventilation After Cardiac Arrest Reduces Oxidation of Brain Lipids and Improves Neurological Outcome • Editorial Comment Stroke, August 1, 1998; 29(8): 1679 - 1686. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Lipscomb, L. G. Gorman, R. J. Traystman, P. D. Hurn, and C. Iadecola Low Molecular Weight Iron in Cerebral Ischemic Acidosis In Vivo • Editorial Comment Stroke, February 1, 1998; 29(2): 487 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Van Bel, M. Shadid, R. M. W. Moison, C. A. Dorrepaal, J. Fontijn, L. Monteiro, M. Van De Bor, and H. M. Berger Effect of Allopurinol on Postasphyxial Free Radical Formation, Cerebral Hemodynamics, and Electrical Brain Activity Pediatrics, February 1, 1998; 101(2): 185 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kim, R. C. Koehler, P. D. Hurn, E. D. Hall, and R. J. Traystman Amelioration of Impaired Cerebral Metabolism After Severe Acidotic Ischemia by Tirilazad Posttreatment in Dogs Stroke, January 1, 1996; 27(1): 114 - 121. [Abstract] [Full Text]
|
|