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 Hunt͞Hess 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.

Intense Correlation Between Brain Infarction and Protein-Conjugated Acrolein

“…1 There are reports that 3-aminopropanal, which automatically produces acrolein, is generated from spermine and is strongly involved in cell damage during ischemia in rats. 26 Accordingly, data obtained thus far strongly suggest that acrolein is mainly produced from spermine and spermidine.…”

“…1 There are reports that 3-aminopropanal, which automatically produces acrolein, is generated from spermine and is strongly involved in cell damage during ischemia in rats. 26 Accordingly, data obtained thus far strongly suggest that acrolein is mainly produced from spermine and spermidine.There is a report that SSAT and SMO are induced during kidney ischemia-reperfusion injury in rats. 27 However, the activity of SSAT, AcPAO, and SMO at the locus of infarction only slightly increased compared with the activity at the same locus of control mice.…”

Polyamine Oxidase and Acrolein as Novel Biochemical Markers for Diagnosis of Cerebral Stroke

“…12,13 It has been reported that acrolein can also be produced from membrane phospholipids, although the major aldehydes produced during lipid peroxidation are 4-hydroxy-2-nonenal and malondialdehyde. 14 We measured acrolein produced from arachidonic acid under the same conditions in which acrolein has been reported to be produced from membrane phospholipids.…”

Anticancer system created by acrolein and hydroxyl radical generated in enzymatic oxidation of spermine and other biochemical reactions

“…Since acrolein is known to be spontaneously generated from 3-substituted propanals [11] and that 3-aminopropanal and H 2 O 2 , the ÅOH radical precursor, are co-generated in spermine enzymatic oxidations by SMO and PAO, the involvement of acrolein and ÅOH radical in the reported cellular deaths in these episodes, appear to be the most likely explanation. A conclusion supported by the observed neutralization of the resulting cytotoxicity with sulfhydryl compounds [89], chemicals that rapid and preferentially reacts with acrolein. Subsequent reports on increases in spermine-oxidase activities and acrolein protein complexes in the blood of patients with strokes [90,91], strongly further support the involvement of acrolein and ÅOH radical in these ischemic events.…”