Glutamate (GLU) “excitotoxicity” stimulates B-aggrecan chondroitin sulfate proteoglycan (CSPG) synthesis in chick neurons at the level of transcription (Krueger and Schwartz (1995), Ped. Res. 37:381A). We hypothesize that B-aggrecan synthesis may be stimulated as a defense against neuronal injury or death. B-aggrecan synthesis in neurons was measured after exposure to specific GLU ionotropic agonists, to hypoxia induced by cyanide, or to agents which induce apoptosis. E6C5 chick neurons were incubated for 30 min with 50 mcM of either GLU, NMDA, or kainate (KA), or 1mM NaCN, returned to the 35S-sulfate containing media, and analyzed at 24 hours. Alternatively, cells were exposed to either 2 mcM Wortmannin or 200 nM Staurosporin, agents which induce apoptosis in this system, for 24 hours in the presence of label. Viability was determined at 24 hr by MTT assay. B-aggrecan and the HNK-1 CSPG were assayed by immunoprecipitation, and radioactivity assayed. Glycosaminoglyacans (GAG) were quantified by CPC precipitation. GLU, NMDA, and KA exposure increased B-aggrecan synthesis in these cultures (KA>GLU>NMDA; p<0.03), above GAG and HNK-1 CSPG synthesis, despite a decrease in neuronal viability. B-aggrecan synthesis is also increased after hypoxic injury. Agents which induce apoptosis significantly decrease B-aggrecan synthesis (p<0.03). After Wortmannin treatment B-aggrecan synthesis is reduced >70%, despite only 25% neuronal death. B-aggrecan synthesis is upregulated after GLU-receptor stimulation or hypoxia more than GAG or HNK-1 CSPG synthesis. Conversely, B-aggrecan is downregulated in apoptosis more than GAG or HNK-1 CSPG synthesis. Finally, apoptosis turns off B-aggrecan synthesis, whereas GLU-receptor stimulation and hypoxia increase synthesis. These data suggest that it is injury and/or ionotropic activation, not neuronal dying, which stimulate CSPG/B-aggrecan synthesis. These data are consistent with the hypothesis that B-aggrecan may have a special role in CNS protection and/or healing. Supported by HD-09402 and Wyeth Neonatal Research fund.