Introduction: Spreading depression (SD) is a wave of depolarization, which passes through the brain and depresses neuronal activities. Various mechanisms have been postulated for SD-induced neurotoxicity. Some of these pathways include ionic imbalances, intracellular calcium accumulation and bioelectrical changes. The hippocampus is one of the most sensitive regions of the brain for SD injuries as the first signs of tissue damage appear in this subcortical structure. Correlations between hippocampal injuries and some neurodegenerative disease have been previously suggested. Inflammatory responses may trigger hippocampal injuries after SD. Materials & Methods: In the present study 36 Wistar rats were treated by dexamethasone before induction of SD to investigate the role of inflammatory responses in SD-induced neurotoxicity. Results: Histological assessments indicated that neural cell death was significantly reduced by pretreatment of dexamethasone. Conclusion: This suggested the possible role for inflammatory response in cell injuries after SD induction.