Brain polyamines are controlled by N-methyl-D-aspartate receptors during ischemia and recirculation.
We studied the time course and molecular mechanisms of changes in brain polyamines and their rate-regulatory synthetic enzyme ornithine decarboxylase during reversible forebrain ischemia and recirculation in the gerbil. Bilateral carotid occlusion induced an acute (less than 2 minutes), transient increase in ornithine decarboxylase activity and putrescine level. After 15 minutes of ischemia, recirculation evoked an immediate (less than 1 minute) increase in ornithine decarboxylase activity and putrescine concentration that progressed over a 15-minute period. A small rise in spermidine and spermine also was observed. A secondary increase in ornithine decarboxylase activity and the levels of putrescine and spermidine commenced after 6 hours of recirculation. Pretreatment with a-difluoromethylornithine, a specific suicide inhibitor of ornithine decarboxylase, or MK-801, a noncompetitive N-methyl-D-aspartate receptor antagonist, abolished all early and delayed increases in ornithine decarboxylase activity and polyamine levels. This is the first demonstration that both ischemia and postischemic recirculation evoke rapid, transient increases in the activity of ornithine decarboxylase and the levels of polyamines, most notably the ornithine decarboxylase product, putrescine. Our results indicate that N-methyl-D-aspartate receptor activation (by an ischemically induced elevation of extracellular glutamate) is responsible for initiating the early and the delayed stimulation of ornithine decarboxylase activity. Ornithine decarboxylase activation causes the rapid rise in the levels of putrescine and higher polyamines observed in the acute response to ischemia and the acute and delayed response to postischemic recirculation. These polyamine changes may be involved in the pathophysiology of Ca2+ entry and neuronal death after brain ischemia.
Koenig
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Neurology Service, VA Lakeside Medical Center, Chicago, IL 60611.
Goldstone
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Trout
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D000818:Animals; D001921:Brain / Q000503:physiopathology; D002545:Brain Ischemia / Q000201:enzymology* / Q000378:metabolism; D002560:Cerebrovascular Circulation; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005260:Female; D005849:Gerbillinae; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D011073:Polyamines / Q000378:metabolism*; D011700:Putrescine / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D009955:Ornithine Decarboxylase; D011700:Putrescine