Neuronal damage after seizure is correlated with blood-brain barrier (BBB) leakage. Adiponectin (Ad) has shown protective effects on endothelial function. In this study, we investigated the effects of Ad on cell survival and BBB integrity in the mouse hippocampus after kainic acid (KA) treatment. Twenty-four hours after intracerebroventricular injection of recombinant Ad, mice were treated with KA, and then sacrificed 48 h later. Decreased serum Ad and increased hippocampal Ad receptor 1 in the hippocampus of KA-treated mice were prevented by Ad pretreatment. Using cresyl violet staining, TUNEL analysis, and immunostaining for caspase-3, histological evaluation revealed that the marked cell death noted in the hippocampus of KA-treated mice was not observed in KA-treated mice pretreated with Ad. Impairment of the BBB, which was demonstrated by the presence of IgG, was inhibited by Ad pretreatment. Immunohistochemical analysis indicated that KA caused up-regulation of hippocampal VEGF, eNOS, and NF-kappaB levels, all of which were reduced in animals that received Ad pretreatment. These data indicate that Ad preserves the integrity of the BBB and has neuroprotective effects in an animal model of seizures.