|
|
|
|
|
|
|
||
J. Exp. Med.,
Volume 188, Number 2, July 20, 1998 327-340
By
From the * Laboratory of Biomedical Science, The Picower Institute for Medical Research, Manhasset,
New York 11030; the 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.
Department of Physiology and the § Department of Neurology, University of
Minnesota, Minneapolis, Minnesota 55455; the Department of Pediatrics, Baylor College of Medicine,
Houston, Texas 77030; the ¶ Department of Surgery, North Shore University Hospital-New York
University Medical School, Manhasset, New York 11030; the ** Department of Experimental
Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208; and the Division of Biology and Human Genetics, Laboratory of Organic Chemistry, The Picower Institute for
Medical Research, Manhasset, New York 11030
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
| TABLE OF CONTENTS |
|
