In spite of recent advances in the treatment of epilepsy, up to 35% of people living with the condition do not respond to accessible anti-epileptic drugs (AEDs) and continue to experience regular, devastating and potentially life-threatening seizures. Neuronal death is a significant feature of epilepsy in humans and experimental models. It has been reported that apelin, an endogenous ligand for the angiotensin-1-like receptor (APJ), has anticonvulsive as well as protective effects in some neurodegenerative situations. In the current study, we investigated the effects of apelin-13 on pentylenetetrazole (PTZ)-induced neurotoxicity in rat’s brain primary culture. Cell injury was induced by 20mM PTZ and the cells viability was examined by MTT assay. Intracellular calcium, reactive oxygen species (ROS) and mitochondrial membrane potential were determined by fluorescence spectrophotometry methods. Markers of apoptosis were determined by immunohistochemistry. The data showed that PTZ caused a loss of cell viability and mitochondrial membrane potential. In addition, intracellular reactive oxygen species, intracellular calcium, COX-2 and caspase-3 positive cells were increased in PTZ-treated cells. Incubation of the cells with aplein-13 (10μM) elicited protective effect and reduced markers of cell damage and death. The results suggest that apelin-13 has protective effects against PTZ-induced toxicity and such effects are accompanied by its calcium blocking, antioxidant and, anti-inflammatory and anti-apoptotic properties.