• 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, and Kevin J Tracey.
• Laboratory of Biomedical Science, North Shore-Long Island Jewish Research Institute, Manhasset, NY 11030, USA. sivanova@nshs.edu
• Proc. Natl. Acad. Sci. U.S.A. 2002 Apr 16;99(8):5579-84.

AbstractCerebral 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.

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