Neuronal toxicity of cyanide in NG108-15 neuroblastoma cells

The effects of sodium cyanide (CN, 0.1-10 mM) were studied on the action potentials elicited by stimulation of hybrid NG108-15 neuroblastoma cells differentiated with 1 mM dibutyryl cAMP. Concentration of CN less than 2 mM had no effect on the amplitude or time course of Na+ and Ca2+ spikes. In a suppopulation of cells showing repetitive discharges elicited by a single pulse, CN (2-10 mM), reversibly abolished repetitive firing within 15 min. In cells exhibiting a single action potential with no repetitive firing, CN up to 10 mM produced no change in the amplitude or time course of Na+ and Ca2+ spikes. In both classes of cells, stimulation at 1 Hz in the presence of CN (up to 5 mM) produced no appreciable use-dependent depression of either Na+ or Ca2+ spike. The ATP and phosphocreatine levels were not depressed in NG108-15 cells exposed to CN (0.1-10 mM) for up to 45 min. Action-potential-generating mechanisms were not depressed by CN when ATP reserves in the cells were greatly depleted by prior exposure to the glycolytic inhibitor 2-deoxyglucose (2-DG). The only significant change was that in the presence of 2-DG cessation of repetitive discharges to single stimuli occurred, even in 0.2 mM CN. This action is most likely due to a reversible depression of the spike after-hyperpolarization. In general, metabolic processes that maintain ionic gradients across the membrane do not appear to be affected by CN at concentrations used in this study, as indicated by the maintenance of membrane potential and the persistence of action-potential generation. It appears that when the oxidative metabolic pathway is blocked by CN via inhibition of cytochrome-e oxidase, energy needs in NG 108-15 cells are met by glycolysis, which is able to sustain the physiological activity of the cell. When both oxidative and glycolytic pathways are blocked by CN and 2-DG, respectively, cellular function continues to be maintained for at least some time despite severely reduced metabolic reserves.