Non-linear effects of cycloheximide in glutamate-treated cultured rat cerebellar neurons

Multiple cell types and organisms across a wide array of phyla and a variety of toxins demonstrate non-linear dose responses to low-level chemical exposures with high doses inhibiting cellular function and low doses stimulating function. We tested whether such non-linear responses to low and ultra-low dose N-methyl-D-aspartate (NMDA), 1-methyl-4-phenylpyridinium (MPP⁺) or cycloheximide moderated toxic glutamate exposure in cultured cerebellar granule cells. Neurons were incubated over 72 h with successive NMDA, MPP⁺ iodide or cycloheximide additions producing specified low (10^-5, 10^-7, 10^-9, 10^-11, and 10^-13 M) and ultra-low (10^-27, 10^-29, 10^-63, and 10-65 M) concentrations. Subsequently these neuronal cells were exposed to a 50% excitotoxic concentration of glutamate for 24 h. Neuronal viability was significantly reduced in neurons treated with micromolar (10^-5 M) cycloheximide whereas viability was enhanced in neurons treated with an ultra-low dose exposure of 10^-27 M cycloheximide. Neither NMDA nor MPP⁺ elicited harmful or protective responses. This is the first report demonstrating non-linear dose-response effects of cycloheximide in low and ultra-low concentration ranges.