Peripheral neuropathy is a significant dose-limiting side effect of the nitroimidazole drugs in vivo. We have thus undertaken a study on the mechanisms of nitroimidazole neurotoxicity in the cultured neuronal cell lines, PC-12 (rat pheochromocytoma) and NB4183 (mouse neuroblastoma). Cells were differentiated with either nerve growth factor or dibutyryl cAMP and then were exposed to misonidazole and SR 2508. Cells underwent extensive morphological changes following exposure to nitroimidazole drugs, including loss of differentiated neurite projections. Loss of neurites appeared to correlate with changes in neurofilament proteins. Immunoblot analysis of the neurofilament proteins revealed a loss of the major parent proteins and the appearance of lower molecular weight (degradation) fragments. Our preliminary data in cultured neuronal cell lines suggest that nitroimidazoles cause disruption and degradation of the neurofilament lattice with subsequent degeneration of dendritic projections, and provide an in vitro model for studying the cellular and biochemical mechanisms of drug-induced neurotoxicity.