We investigated the role of phosphacan, a chondroitin sulfate proteoglycan that is constitutively expressed in the adult hippocampus, and recombinant core proteins of phosphacan in excitotoxic cell death of primary cultured rat hippocampal neurons. Phosphacan had no significant effect on excitotoxic neuronal death. Surprisingly, one of three recombinant proteins corresponding to N-terminal portions of phosphacan core protein dramatically promoted excitotoxic neuronal death. Moreover, the recombinant protein induced cell death of rat hippocampal neurons, even when neurons were not exposed to glutamate. These results suggest that proteolytic degradation of phosphacan and resultant core protein fragments may contribute to neuronal degeneration of hippocampal neurons in various neuropathological conditions.