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Background: In the present study the effect of Salvia rhytidia extract on thickness of cerebral cortex and hippocampal regions following ischemia-reperfusion (IR) injuries is evaluated. Objectives: In the present study the extract of S. rhytidia, an endemic plant from south eastern of Iran, was used to prevent IR injuries induced in cerebral cortex and hippocampus of rats. Materials and Methods:In this cross-sectional study, 35 male healthy Wistar rats between 250 -350 g were randomly divided into 7 groups of 5 rats. Control group (A), ischemic groups (B, D, E, F, G) that left common carotid and left vertebral arteries were occluded for 10 minutes. Group D received S. rhytidia extract (3.2 mg/kg) and group E received silymarin (50 mg/kg), a chemical drug which is used for reducing oxidative stress, 2 hours after ischemia, whereas group F received S. rhytidia extract (3.2 mg/kg) and group G received silymarin (50 mg/kg), 72, 48, 24 and 0 hours before ischemia. Group B received no drug and sham group (C) received normal saline (NS) without ischemia. After 24 hours reperfusion, the brains of rats were prepared for histological studies and the data were analyzed using one way ANOVA and Duncan as posthoc test. Results: IR resulted in decrease in thickness of the cerebral cortex, CA1 and CA2 regions of the hippocampus in groups B, D and E compared to control (P < 0.05). But no significant decrease observed in thickness of the cerebral cortex and all hippocampal regions in groups C, F, G and CA3 and dentate gyrus regions of the hippocampus in groups B, D and E compared to control. Conclusions: This study showed that S. rhytidia extract can protect the forebrain from IR injuries due to antioxidative effect of the drug.