MECHANISMS OF NEURONAL death after acute insults are unknown but may involve energy depletion and resultant glutamate toxicity. One potential pathway leading to cell death is the formation of oxygen free radicals in an energy-depleted state. Megadoses of glucocorticoids as well as the lazaroid compounds (e.g., 21-aminosteroids and 2-methylaminochromans) have been shown to be potent antioxidants, capable of mitigating the effects of oxygen radicals on lipid membranes in vitro. The authors investigated the protective antioxidant effects of megadose methylprednisolone (MPSS) and the lazaroid 2-methylaminochroman (U-78517F) on the size of striatal lesions caused by quinolinic acid, an N-methyl-D-aspartate (NMDA) receptor agonist that mimics certain aspects of the secondary injury surrounding the pan-necrosis central to stroke or cerebral contusion. Treatment with MPSS (60 mg/kg/day) before quinolinate infusion and continuing through the first postoperative day caused a significant (P < 0.01) 56% increase in the size of striatal lesions. In contrast, treatment with MPSS given 2 to 6 hours after creation of the lesion did not affect lesion size. Animals treated with U-78517F also failed to exhibit any neuroprotective effects. The detrimental effect of pretreatment with megadose MPSS is likely the result of deleterious energy-depleting glucocorticoid effects that outweigh any positive antioxidant effects. We conclude that megadose MPSS, although found to be beneficial in the treatment of spinal cord injury, may not be beneficial in the treatment of intracranial insults involving glutamate toxicity.