The generation of free radicals in the progression of kainic acid (KA)-mediated neuronal death has been implicated in both in vitro and in vivo studies. In the present study, the association between KA-induced neurodegeneration and the appearance of lipid peroxidation products was investigated and compared to three well characterized free radical generating (FRG) systems: 200 microM ferrous ammonium sulfate (FAS), 20 microM copper (Cu2+), and 0.01 U/ml xanthine oxidase/2.3 mM purine/2.4 microM transferrin (XO). KA caused a dose-dependent increase in conjugated diene and lipid hydroperoxide formation as did the FRG systems. The antioxidant, butylated hydroxytoluene (BHT), decreased both FRG system- and KA-induced lipid peroxidation by approximately 60-70%. Unlike BHT, the potency of the lipid peroxidation inhibitor, U78517F, depended upon the system utilized to induce free radical generation. U78517F was most potent in attenuating FAS-induced lipid peroxidation (100 nM), followed by KA (1.5 microM), and then Cu2+ and XO (> 2 microM). Results were confirmed by measurement of cytolysis through the release of lactic dehydrogenase (LDH). These data provide further evidence that the generation of free radicals, subsequently leading to membrane disruption, is central to the mechanism of KA-elicited neuronal death in cultures of cerebellar granule cells.