N-methyl-D-aspartate receptor excitotoxicity involves activation of polyamine synthesis: protection by alpha-difluoromethylornithine.
We investigated the role of polyamines and their regulatory enzyme ornithine decarboxylase in N-methyl-D-aspartate-induced excitotoxicity in embryonic chick retina. N-Methyl-D-aspartate (200 microM) produced an early increase in ornithine decarboxylase activity, putrescine concentration, and Ca2+ entry, leading to selective neuronal death by 30 min. This response was attenuated by the ornithine decarboxylase inhibitor alpha-difluoromethylornithine and the N-methyl-D-aspartate receptor antagonist 5-aminophosphonovaleric acid. Exogenous putrescine increased intracellular putrescine and spermine levels and reversed neuroprotection by alpha-difluoromethylornithine, but not by 5-aminophosphonovaleric acid. N-Methyl-D-aspartate-receptor stimulation of putrescine/polyamine synthesis mediates abnormal Ca2+ entry and acute excitotoxic neuronal death. Postreceptor inhibition of the ornithine decarboxylase/polyamine cascade by alpha-difluoromethylornithine may provide neuroprotection against N-methyl-D-aspartate-induced excitotoxicity.
Trout
J J
JJ
Research Service, V.A. Lakeside Medical Center, Chicago, IL 60611.
Koenig
H
H
Goldstone
A D
AD
Iqbal
Z
Z
Lu
C Y
CY
Siddiqui
F
F
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002642:Chick Embryo; D000518:Eflornithine / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology; D009498:Neurotoxins / Q000378:metabolism*; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism*; D011700:Putrescine / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D012160:Retina / Q000378:metabolism
D009498:Neurotoxins; D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D007770:L-Lactate Dehydrogenase; D009955:Ornithine Decarboxylase; D002118:Calcium; D011700:Putrescine; D000518:Eflornithine