Release of endogenous polyamines may contribute to neuronal loss in ischemia and related conditions. Primary cortical neurons were exposed to spermine and spermidine and subsequently assayed for [3H]ouabain binding to quantify neuronal loss. Neuronal survival was significantly decreased in the presence of spermine at 24 h (500 microM), 48 h (250 microM and 500 microM) and 72 h (10-500 microM) relative to controls. Co-application of 250 microM spermine and 10 microM dizocilpine for 48 h completely inhibited the effect of spermine alone. Spermidine exposure (10-500 microM) did not alter neuronal survival at any of the time points. These data indicate that the polyamine spermine is toxic to neurons in vitro and that toxicity is prevented by the NMDA-associated channel antagonist dizocilpine.