Cerebral ischemia enhances polyamine oxidation: identification of enzymatically formed 3-aminopropanal as an endogenous mediator of neuronal and glial cell death.
To elucidate endogenous mechanisms underlying cerebral damage during ischemia, brain polyamine oxidase activity was measured in rats subjected to permanent occlusion of the middle cerebral artery. Brain polyamine oxidase activity was increased significantly within 2 h after the onset of ischemia in brain homogenates (15.8 +/- 0.9 nmol/h/mg protein) as compared with homogenates prepared from the normally perfused contralateral side (7.4 +/- 0.5 nmol/h/mg protein) (P <0.05). The major catabolic products of polyamine oxidase are putrescine and 3-aminopropanal. Although 3-aminopropanal is a potent cytotoxin, essential information was previously lacking on whether 3-aminopropanal is produced during cerebral ischemia. We now report that 3-aminopropanal accumulates in the ischemic brain within 2 h after permanent forebrain ischemia in rats. Cytotoxic levels of 3-aminopropanal are achieved before the onset of significant cerebral cell damage, and increase in a time-dependent manner with spreading neuronal and glial cell death. Glial cell cultures exposed to 3-aminopropanal undergo apoptosis (LD50 = 160 microM), whereas neurons are killed by necrotic mechanisms (LD50 = 90 microM). The tetrapeptide caspase 1 inhibitor (Ac-YVAD-CMK) prevents 3-aminopropanal-mediated apoptosis in glial cells. Finally, treatment of rats with two structurally distinct inhibitors of polyamine oxidase (aminoguanidine and chloroquine) attenuates brain polyamine oxidase activity, prevents the production of 3-aminopropanal, and significantly protects against the development of ischemic brain damage in vivo. Considered together, these results indicate that polyamine oxidase-derived 3-aminopropanal is a mediator of the brain damaging sequelae of cerebral ischemia, which can be therapeutically modulated.
Ivanova
S
S
Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset, New York 11030, USA.
Botchkina
G I
GI
Al-Abed
Y
Y
Meistrell
M
M
Batliwalla
F
F
Dubinsky
J M
JM
Iadecola
C
C
Wang
H
H
Gregersen
P K
PK
Eaton
J W
JW
Tracey
K J
KJ
D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death; D002460:Cell Line; D009682:Magnetic Resonance Spectroscopy; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000378:metabolism*; D011437:Propylamines / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D013096:Spermine / Q000378:metabolism*; D000097667:Polyamine Oxidase
D000447:Aldehydes; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011437:Propylamines; D013096:Spermine; D000097667:Polyamine Oxidase; C050862:3-aminopropionaldehyde