title: N-methyl-D-aspartate receptor excitotoxicity involves activation of polyamine synthesis: protection by alpha-difluoromethylornithine.
abstract: 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.
authors.affiliation: Research Service, V.A. Lakeside Medical Center, Chicago, IL 60611.
authors.forename: J J
authors.initials: JJ
authors.lastname: Trout
authors.forename: H
authors.initials: H
authors.lastname: Koenig
authors.forename: A D
authors.initials: AD
authors.lastname: Goldstone
authors.forename: Z
authors.initials: Z
authors.lastname: Iqbal
authors.forename: C Y
authors.initials: CY
authors.lastname: Lu
authors.forename: F
authors.initials: F
authors.lastname: Siddiqui
mesh_terms: 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
chemical_list: 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