To elucidate endogenous mechanisms underlying cerebral damage during ischemia, brain polyamine oxidase activity was measured in rats subjected to permanent occlusion of the middle cerebral artery. Brain polyamine oxidase activity was increased significantly within 2 h after the onset of ischemia in brain homogenates (15.8 ± 0.9 nmol/h/mg protein) as compared with homogenates prepared from the normally perfused contralateral side (7.4 ± 0.5 nmol/h/mg protein) (P <0.05). The major catabolic products of polyamine oxidase are putrescine and 3-aminopropanal. Although 3-aminopropanal is a potent cytotoxin, essential information was previously lacking on whether 3-aminopropanal is produced during cerebral ischemia. We now report that 3-aminopropanal accumulates in the ischemic brain within 2 h after permanent forebrain ischemia in rats. Cytotoxic levels of 3-aminopropanal are achieved before the onset of significant cerebral cell damage, and increase in a time-dependent manner with spreading neuronal and glial cell death. Glial cell cultures exposed to 3-aminopropanal undergo apoptosis (LD50 = 160 μM), whereas neurons are killed by necrotic mechanisms (LD50 = 90 μM). The tetrapeptide caspase 1 inhibitor (Ac-YVAD-CMK) prevents 3-aminopropanal–mediated apoptosis in glial cells. Finally, treatment of rats with two structurally distinct inhibitors of polyamine oxidase (aminoguanidine and chloroquine) attenuates brain polyamine oxidase activity, prevents the production of 3-aminopropanal, and significantly protects against the development of ischemic brain damage in vivo. Considered together, these results indicate that polyamine oxidase–derived 3-aminopropanal is a mediator of the brain damaging sequelae of cerebral ischemia, which can be therapeutically modulated.
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20 July 1998
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July 20 1998
Cerebral Ischemia Enhances Polyamine Oxidation: Identification of Enzymatically Formed 3-Aminopropanal as an Endogenous Mediator of Neuronal and Glial Cell Death
Svetlana Ivanova,
Svetlana Ivanova
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
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Galina I. Botchkina,
Galina I. Botchkina
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
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Yousef Al-Abed,
Yousef Al-Abed
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
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Malcolm Meistrell, III,
Malcolm Meistrell, III
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
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Franak Batliwalla,
Franak Batliwalla
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
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Janet M. Dubinsky,
Janet M. Dubinsky
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
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Constantino Iadecola,
Constantino Iadecola
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
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Haichao Wang,
Haichao Wang
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
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Peter K. Gregersen,
Peter K. Gregersen
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
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John W. Eaton,
John W. Eaton
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
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Kevin J. Tracey
Kevin J. Tracey
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
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Svetlana Ivanova
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
Galina I. Botchkina
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
Yousef Al-Abed
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
Malcolm Meistrell, III
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
Franak Batliwalla
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
Janet M. Dubinsky
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
Constantino Iadecola
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
Haichao Wang
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
Peter K. Gregersen
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
John W. Eaton
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
Kevin J. Tracey
From the *Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030; the ‡Department of Physiology and the §Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455; the ‖Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030; the ¶Department of Surgery, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; the **Department of Experimental Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the ††Division of Biology and Human Genetics, Department of Medicine, and the §§Department of Emergency Medicine, North Shore University Hospital–New York University Medical School, Manhasset, New York 11030; and the ∥∥Laboratory of Organic Chemistry, The Picower Institute for Medical Research, Manhasset, New York 11030
Address correspondence to Kevin J. Tracey, The Picower Institute for Medical Research, 350 Community Dr., Manhasset, NY 11030. Phone: 516-562-9476; Fax: 516-562-2356; E-mail: [email protected]
Received:
February 10 1998
Revision Received:
May 06 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 188 (2): 327–340.
Article history
Received:
February 10 1998
Revision Received:
May 06 1998
Citation
Svetlana Ivanova, Galina I. Botchkina, Yousef Al-Abed, Malcolm Meistrell, Franak Batliwalla, Janet M. Dubinsky, Constantino Iadecola, Haichao Wang, Peter K. Gregersen, John W. Eaton, Kevin J. Tracey; Cerebral Ischemia Enhances Polyamine Oxidation: Identification of Enzymatically Formed 3-Aminopropanal as an Endogenous Mediator of Neuronal and Glial Cell Death . J Exp Med 20 July 1998; 188 (2): 327–340. doi: https://doi.org/10.1084/jem.188.2.327
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