Doxorubicin intoxication: neurofilamentous axonal changes with subacute neuronal death

Neurofilamentous axonal swellings occur in various chronic neuronal degenerations in man and animals. The pathogenesis of these swellings in the setting of neuronal degeneration remains unclear. A toxic model of neuronal degeneration can be produced by doxorubicin. This agent impairs DNA-dependent RNA synthesis and produces subacute neuronal death. The aim of the present study was to investigate whether neurofilamentous axonal swellings occur in association with neuronal nuclear derangement and subacute neuronal death produced by doxorubicin. We investigated the evolution of changes seen in retinal ganglion cells and their axons after an intravitreous injection of doxorubicin in rats. The earliest changes were in the nuclei of the retinal ganglion cells. Later, transient axonal swellings filled with neurofilaments were prominent. These neurofilamentous swellings preceded the subacute neuronal cell death. To determine whether these changes represent a direct effect of the agent on the axon, we injected doxorubicin directly into the sciatic nerve. This local injection did not produce similar changes in the axons. These results suggest that in this model neurofilamentous axonal swellings precede neuronal cell death and may be due to a primary insult to the nerve cell body.