Non-Linear Effects of Cycloheximide in Glutamate-Treated Cultured Rat Cerebellar Neurons

Abstract

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.