Increased release of glutamate is thought to contribute to ischemia-induced neuronal damage. Since general anesthetics such as thiopental and ketamine are thought to provide some degree of cerebral protection, this study was intended to 1) compare the effectiveness of ketamine and thiopental on ischemia-induced tissue damage; and, if so, 2) determine whether attenuation of the increased amino acid release is the sole mechanism for the protective effects demonstrated. Striatal slices prepared from Wistar Albino rats were incubated in an ischemic medium for 1 hour followed by 5 hours in a reoxygenation (REO) medium. Ketamine and thiopental were added medium during ischemia and/or REO periods, and the medium was collected at the end of each incubation period for measurement of amino acid release and lactate dehydrogenase (LDH) leakage. Ischemia significantly increased amino acid release without altering LDH leakage. Ischemia-induced increments in glutamate and aspartic acid releases returned to control levels during REO, but LDH leakage increased (P < 0.001) during this period. Although ketamine (100 muM) and thiopental (100 mu\M) failed to decrease ischermia-induced excitatory amino acid release, they protected the slices against REO-induced LDH leakage. Ketamine, but not thiopental, was effective even if added after ischemia (P < 0.05). These results indicate that ketamine and thiopental protect the slices against REO-induced LDH leakage. However, mechanisms other than attenuation of the enhanced glutamate release might be responsible for their protective effects.