Seizurogenic activity develops in many patients following brain injury and may be involved in the pathophysiological effects of brain trauma and stroke. We have evaluated the effects of the use-dependent sodium channel blocker RS100642, an analog of mexiletine, as a neuroprotectant and anti-seizure agent in a rat model of transient middle cerebral artery occlusion (MCAo). Post-injury treatment with RS100642 (0.01-5.0 mg/kg) dose-dependently reduced brain infarction, improved functional recovery of electroencephalographic (EEG) power, and improved neurological outcome following 2 h of MCAo and 24 h recovery. This effect was more potent and offered a larger reduction of brain infarct volume than a maximal neuroprotective dose of mexiletine (10.0 mg/kg). Furthermore, brain seizure activity recorded following 1 h MCAo and 72 h of recovery in injured rats was either completely blocked (30 min pre-MCAo treatment) or significantly reduced (30 min post-MCAo treatment) with RS100642 (1.0 mg/kg) treatment resulting in greater than 60% reduction of core brain infarct. These results indicate that brain seizure activity during MCAo likely contributes to the pathophysiology of brain injury and that RS100642 may be an effective neuroprotective treatment not only to decrease brain injury but also to reduce the pathological EEG associated with focal ischemia.