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, Kevin J. Tracey

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)5579-5584
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number8
DOIs
StatePublished - Apr 16 2002

ASJC Scopus subject areas

  • General

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