Induction of ornithine decarboxylase by N-methyl-D-aspartate receptor activation is unrelated to potentiation of glutamate excitotoxicity by polyamines in cerebellar granule neurons.
Polyamines positively modulate the activity of the N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors. The concentration of polyamines in the brain increases in certain pathological conditions, such as ischemia and brain trauma, and these compounds have been postulated to play a role in excitotoxic neuronal death. In primary cultures of rat cerebellar granule neurons, exogenous application of the polyamines spermidine and spermine (but not putrescine) potentiated the delayed neurotoxicity elicited by NMDA receptor stimulation with glutamate. Furthermore, both toxic and nontoxic concentrations of glutamate stimulated the activity of ornithine decarboxylase (ODC)--the key regulatory enzyme in polyamine synthesis--and increased the concentration of ODC mRNA in cerebellar granule neurons but not in glial cells. Glutamate-induced ODC activation but not neurotoxicity was blocked by the ODC inhibitor difluoromethylornithine. Thus, high extracellular polyamine concentrations potentiate glutamate-triggered neuronal death, but the glutamate-induced increase in neuronal ODC activity may not play a determinant role in the cascade of intracellular events responsible for delayed excitotoxicity.
Lombardi
G
G
Fidia-Georgetown Institute for the Neurosciences, Georgetown University, Washington, D.C.
Szekely
A M
AM
Bristol
L A
LA
Guidotti
A
A
Manev
H
H
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000201:enzymology*; D004357:Drug Synergism; D000518:Eflornithine / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005971:Glutamates / Q000494:pharmacology*; D018698:Glutamic Acid; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D009955:Ornithine Decarboxylase / Q000096:biosynthesis* / Q000235:genetics; D011073:Polyamines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D013095:Spermidine / Q000494:pharmacology; D013096:Spermine / Q000494:pharmacology
D005971:Glutamates; D011073:Polyamines; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D013096:Spermine; D018698:Glutamic Acid; D009955:Ornithine Decarboxylase; D013095:Spermidine; D000518:Eflornithine