Neuroprotection in cerebral ischemia by neutralization of 3-aminopropanal.

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.

• Authors: 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, Kevin J Tracey
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 99 Issue 8 Pg. 5579-84 (Apr 16 2002) ISSN: 0027-8424 [Print] United States
• PMID: 11943872 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Aldehydes
• Antioxidants
• N-(2-mercaptoproprionyl)-glycine
• Propylamines
• Sulfhydryl Compounds
• 3-aminopropionaldehyde
• Glycine

Topics

• Aldehydes (metabolism)
• Animals
• Antioxidants (pharmacology)
• Brain (pathology)
• Brain Ischemia (prevention & control)
• Cell Line
• Cells, Cultured
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Glycine (analogs & derivatives, pharmacology)
• Humans
• Immunoblotting
• In Situ Nick-End Labeling
• Microscopy, Fluorescence
• Models, Chemical
• Neuroglia (metabolism)
• Propylamines (metabolism)
• Protein Binding
• Rats
• Spectrometry, Mass, Electrospray Ionization
• Sulfhydryl Compounds (pharmacology)
• Time Factors