Primary cortical and hippocampal neuronal cultures submitted to brief histotoxic hypoxia suffer delayed neuronal death after 24 h [Uto et al. (1995) J Neurochem 64: 2185-2192]. In this study the ultrastructural changes were monitored during the first 6 h following 5-min histotoxic hypoxia induced by exposure to 100 microM iodoacetate. In both cortical and hippocampal CA1 neurons, disaggregation of ribosomes was the earliest sign of histotoxic pathology. Vacuolizations of mitochondria, endoplasmic reticulum and Golgi apparatus, as well as fragmentation and disintegration of neurofilaments followed later. Signs of apoptotic nuclear degeneration were absent. Our observations demonstrate that, similar to that seen in ischemia, disaggregation of ribosomes after brief histotoxic hypoxia is one of the first pathological alterations heralding delayed neuronal death.