In the present study, melatonin was tested in subsequent doses in glutamate induced neurotoxicity in cerebellar granular cell culture of rat pups. Glutamate at 10(-7) M was found to induce neuronal cell death. The dead cell score was 2.75 +/- 0.7 in the control, while it was found to be 35.12 +/- 1.8 in the glutamate-administered group (P<0.0001). Melatonin very potently blocked glutamate neurotoxicity at all doses tested, with 10(-3) M, the highest dose tested, being the most effective. Glutamate may exert a neuroprotective effect by blocking one or more steps of the oxidation cascade in neurons and this effect may be blocked by melatonin.