TY - JOUR
T1 - Cerebral ischemia enhances polyamine oxidation
T2 - Identification of enzymatically formed 3-aminopropanal as an endogenous mediator of neuronal and glial cell death
AU - Ivanova, Svetlana
AU - Botchkina, Galina I.
AU - Al-Abed, Yousef
AU - Meistrell, Malcolm
AU - Batliwalla, Franak
AU - Dubinsky, Janet M.
AU - Iadecola, Constantino
AU - Wang, Haichao
AU - Gregersen, Peter K.
AU - Eaton, John W.
AU - Tracey, Kevin J.
PY - 1998/7/20
Y1 - 1998/7/20
N2 - 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 μM), whereas neurons are killed by necrotic mechanisms (LD50 = 90 μM). 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.
AB - 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 μM), whereas neurons are killed by necrotic mechanisms (LD50 = 90 μM). 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.
KW - Apoptosis
KW - Caspase
KW - Infarction
KW - Spermine
KW - Stroke
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U2 - 10.1084/jem.188.2.327
DO - 10.1084/jem.188.2.327
M3 - Article
C2 - 9670045
AN - SCOPUS:0031824133
SN - 0022-1007
VL - 188
SP - 327
EP - 340
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 2
ER -