N-methyl-D-aspartate receptor excitotoxicity involves activation of polyamine synthesis: protection by...

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.