Neuroprotection in cerebral ischemia by neutralization of 3-aminopropanal
- Svetlana Ivanova*,†,
- Franak Batliwalla‡,
- J. Mocco§,
- Szilard Kiss§,
- Judy Huang§,
- William Mack§,
- Alexander Coon§,
- John W. Eaton¶,
- Yousef Al-Abed‖,
- Peter K. Gregersen‡,
- Esther Shohami**,
- E. Sander Connolly, Jr.§, and
- Kevin J. Tracey*
- Laboratories of *Biomedical Science and ‖Medicinal Chemistry, and ‡Division of Biology and Human Genetics, North Shore-Long Island Jewish Research Institute, Manhasset, NY 11030; §Department of Neurological Surgery, College of Physicians and Surgeons, Columbia University, New York, NY 10032; ¶James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202; and **Department of Pharmacology, Hebrew University, Jerusalem 91120, Israel
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Edited by Anthony Cerami, The Kenneth S. Warren Institute, Tarrytown, NY, and approved February 14, 2002 (received for review November 14, 2001)
Abstract
Cerebral ischemia stimulates increased activity of polyamine oxidase, a ubiquitous enzyme that catabolizes polyamines to produce 3-aminopropanal. 3-Aminopropanal is a reactive aldehyde that mediates progressive neuronal necrosis and glial apoptosis. Here we report that increased levels of 3-aminopropanal-modified protein levels in humans after aneurysmal subarachnoid hemorrhage correlate with the degree of cerebral injury as measured by admission Hunt/Hess grade. In vitro screening of clinically approved drugs reveals that N-2-mercaptopropionyl glycine (N-2-MPG), an agent clinically approved for prevention of renal stones in patients with cysteinuria, significantly inhibits the cytotoxicity of 3-aminopropanal. N-2-MPG reacts with 3-aminopropanal to yield a nontoxic thioacetal adduct, as confirmed by electrospray ionization mass spectroscopy. Administration of N-2-MPG in clinically relevant doses to rats significantly reduces cerebral 3-aminopropanal-modified protein immunoreactivity and infarct volume in a standardized model of middle cerebral artery occlusion, even when the agent is administered after the onset of ischemia. These results implicate 3-aminopropanal as a therapeutic target for cerebral ischemia.
Footnotes
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↵ † To whom reprint requests should be addressed. E-mail: sivanova{at}nshs.edu.
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This paper was submitted directly (Track II) to the PNAS office.
- Abbreviations:
- PAO,
- polyamine oxidase;
- SAH,
- subarachnoid hemorrhage;
- N-2-MPG,
- N-2-mercaptopropionyl glycine;
- MCAO,
- middle cerebral artery occlusion;
- CSF,
- cerebrospinal fluid
- Copyright © 2002, The National Academy of Sciences
