Levetiracetam, an Antiepileptic Drug has Neuroprotective Effects on Intracranial Hemorrhage Injury

•Levetiracetam suppressed brain edema formation and neurological deficits after intracranial hemorrhage.•Levetiracetam directly protected neuronal injury against both hemoglobin- and hemin-induced damage.•Levetiracetam suppressed apoptosis after intracranial hemorrhage. Intracranial hemorrhage (ICH) is a devastating disease that induces hematoma formation with poor neuronal outcome. Levetiracetam (LEV) has been approval for epilepsy seizures. In a previous study, LEV exerted protective effects on cerebral ischemia models; however, the detail effects and the influence of LEV on ICH are still unknown. The aim of this study was to investigate whether oral administration of LEV (50 or 150 mg/kg) has protective effects on ICH injury using both in vivo and in vitro experiments. In in vivo experiments, we utilized ICH models induced by autologous blood (bICH) or collagenase (cICH) injection. Moreover, we established a neuronal injury model using SYSH5Y human neuroblastoma cell lines. In the bICH model, frequently oral administration of LEV attenuated both cerebral edema and neurological deficits. In addition, the expression levels of phosphorylation-extracellular signal‑related kinase (ERK) 1/2 and cleaved caspase-7 were increased after ICH, and LEV suppressed such alterations. In in vitro experiments, hematoma releasing factors, such as hemoglobin (Hb) and hemin, induced neuronal cell death, and LEV treatment attenuated neuronal injury in a dose-dependent manner. In the cICH model, neurological deficits induced by extensive hematoma formation were attenuated by LEV without affecting hematoma volume. Taken together, these findings suggested that LEV has protective effect on neurons after ICH injury. Therefore, LEV may not only be an efficacious therapeutic agent for seizures, but also for post-hemorrhagic stroke brain injury.