A growing body of evidence suggests that excessive Zn2+ release plays a key role in inducing neuronal death during central nervous system injury. However, the possible cytotoxicity of extracellular Zn2+ to oligodendrocyte lineage cells remains unknown. Employing cultures of rat oligodendrocyte progenitor cells (OPC), we report here that OPC are vulnerable to increased extracellular Zn2+ levels and that pyruvate limits Zn2+-induced OPC death. Zn2+-induced concentration-dependent (pEC50 = -4.1 +/- 0.1) OPC death, which was insensitive to both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (Evans Blue) and l-type Ca2+ channel (nicardipine) inhibition. Neither kainate nor nicardipine influenced OPC 65Zn2+ accumulation, in contrast with the Zn2+ ionophore, pyrithione. Cytotoxic extracellular Zn2+ concentrations failed to increase OPC reactive oxygen species production and the antioxidant reagents, trolox, N,N'-diphenyl-1,4-phenylenediamine and N-tert-butyl-alpha-phenylnitrone did not afford significant protection from Zn2+ insults. The apoptotic inducer staurosporine induced the appearance of known apoptotic markers [pyknotic nuclei and caspase-3 specific (120 kDa) alpha-fodrin cleavage fragment], events not reproduced with Zn2+ insults. Zn2+ insults were also insensitive to the pan-caspase inhibitor Z-VAD-fmk. However, pyruvate afforded significant OPC protection from lethal Zn2+ insults. We conclude that cultured OPC are vulnerable to Zn2+ insults, via a nonoxidative stress and noncaspase-3-based mechanism, involving Zn2+ inhibition of OPC glycolysis.