BACKGROUND: The dysfunction of the proteasome system has been implicated in neuronal degeneration. Apocynin, a specific inhibitor for nicotinamide adenine dinucleotide phosphate oxidase, has anti-inflammatory and anti-oxidant effects. However, the effect of apocynin on the neuronal cell death induced by proteasome inhibition has not been studied. METHODS: Using differentiated PC12 cells, in the respect of cell death process the suppressive effect of apocynin on the proteasome inhibition-mediated apoptosis was examined. RESULTS: The proteasome inhibitors MG132 and MG115 induced a decrease in Bid and Bcl-2 protein levels, an increase in Bax and p53 levels, mitochondrial depolarization, efflux of cytochrome c into cytosol and increase in caspases (-8, -9 and -3) activities. Treatment with apocynin attenuated the proteasome inhibitor-induced changes in the apoptosis-related protein levels, formation of reactive oxygen species, glutathione (GSH) depletion and cell death. CONCLUSIONS: Apocynin may attenuate the proteasome inhibitor-mediated apoptosis in differentiated PC12 cells by inhibiting the activation of the mitochondria-mediated pathway and the caspase-8- and Bid-dependent pathways. The preventive effect of apocynin appears to be attributed to inhibition of the production of reactive oxygen species and the depletion of cellular GSH contents.