To determine the role of tetrodotoxin-sensitive ion channels in post-ischemic selective neuronal death, the effect of tetrodotoxin on ischemia-induced brain cell injury was studied in rats. The animals were subjected to 20 min of cerebral ischemia in a four vessels occlusion model. Thirty min before ischemia, tetrodotoxin at a dose of 10(-7) or 10(-6) M was topically applied into the hippocampal CA1 subfield. Morphological changes in the CA1 subfield were evaluated 7 days after ischemia and compared with those of a vehicle-injected group. The average cell density of CA1 pyramidal neurons ipsilateral to the injection (cells/mm, mean +/- S.E.M.) was 27 +/- 7 (n = 6) in the vehicle-treated group, and 56 +/- 13 (n = 6) and 83 +/- 17 (n = 6) in the group treated with tetrodotoxin at doses of 10(-7) and 10(-6) M, respectively. Tetrodotoxin mitigated the ischemic hippocampal neuronal damage in a limited but dose-dependent manner. This suggests that activation of tetrodotoxin-sensitive ion channels might contribute to the process of the ischemic neuronal damage.