Neuroprotection in cerebral ischemia by neutralization of 3-aminopropanal.
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.
Ivanova
Svetlana
S
Laboratory of Biomedical Science, North Shore-Long Island Jewish Research Institute, Manhasset, NY 11030, USA. sivanova@nshs.edu
Batliwalla
Franak
F
Mocco
J
J
Kiss
Szilard
S
Huang
Judy
J
Mack
William
W
Coon
Alexander
A
Eaton
John W
JW
Al-Abed
Yousef
Y
Gregersen
Peter K
PK
Shohami
Esther
E
Connolly
E Sander
ES
Tracey
Kevin J
KJ
D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000517:prevention & control*; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008856:Microscopy, Fluorescence; D008956:Models, Chemical; D009457:Neuroglia / Q000378:metabolism; D011437:Propylamines / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013997:Time Factors
D000447:Aldehydes; D000975:Antioxidants; C110658:N-(2-mercaptoproprionyl)-glycine; D011437:Propylamines; D013438:Sulfhydryl Compounds; C050862:3-aminopropionaldehyde; D005998:Glycine