Lacosamide, a novel antiepileptic drug, has been discovered to have some beneficial effects beyond its effectiveness. In the present study, we examined the neuroprotective effect of lacosamide against ischemic damage in the hippocampal CA1 region following 5 min of transient cerebral ischemia in gerbils. The results showed that pre- and post-treatment with 25 mg/kg lacosamide protected significantly neuronal death from transient cerebral ischemic injury. Many CV positive cells, NeuN-immunoreactive neurons and a few number of F-J B-positive cells were found in the stratum pyramidale of the CA1 region in the lacosamide-treated ischemia-operated groups compared with those in the vehicle-treated ischemia-operated group. In addition, treatment with lacosamide also markedly attenuated the activation of astrocytes and microglia in the ischemic CA1 region. On the other hand, we examined that treatment with lacosamide increased and maintained the antioxidants levels; and TNF-α and BDNF immunoreactivities were increased significantly after lacosamide treatment following transient cerebral ischemia. In brief, these results indicate that both pre- and post-treatment with lacosamide can protect CA1 pyramidal neurons from transient cerebral ischemic injury in the hippocampus, and the neuroprotective effect of risperidone may be related to the maintenance of antioxidants as well as the increase of TNF-α and BDNF levels.