OBJECTIVE We explored the effectiveness of dual blockade of calcium channels in preventing ischemic necrosis in a rat model of transient forebrain ischemia. METHODS To assess all the major brain regions, the entire brain was subserially sectioned and examined histologically 1 week after ischemia in 44 male Wistar rats. Brain temperature was monitored and controlled to avoid hypothermia or intergroup temperature differences at the time drugs were administered. All regimens were begun 20 minutes after ischemia. Treated animals received either the L-type calcium channel blocker nimodipine (0.25 microgram/min x 24-hour i.v. infusion), the noncompetitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine; 5 mg/kg i.v.), or both regimens in combination. RESULTS In the neocortex (p less than 0.05) and striatum (p less than 0.05), only double-treated animals showed a statistically significant reduction in neuronal necrosis. Dual therapy eliminated neuronal necrosis in the caudate nucleus entirely. In the septal (densely ischemic) hippocampus, protection was weak and inconsistent (0.012 less than p less than 0.788), but in the temporal (incompletely ischemic) hippocampus, the dual-treated group showed the most significant reduction (p less than 0.006). CONCLUSIONS We conclude that the combination of nimodipine and MK-801, if begun 20 minutes after ischemia, may offer a neuroprotective effect against neuronal necrosis in transient forebrain ischemia and that protection is maximal in the major extrahippocampal brain regions.