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Background: Arsenic is a toxic element that widely widespread in environment. Inflammation is now considered as one of the major mechanisms implicated in arsenic poisoning. Curcumin (Cur) and N-acetylcysteine (NAC) are potential antioxidants that protect cells against inflammation. This study aimed to compare the protective effect of Cur and NAC on brain histology and inflammatory factors, including matrix metalloproteinases-2, -9 (MMP-2, 9) and tumor necrosis factor-α (TNF-α) in rats exposed to single dose of arsenic. Methods: Rats were exposed to single dose of arsenic (20mg/kg, by gavage) for 30 days and then treated with 300mg/kg NAC (by gavage) and 100mg/kg Cur (by gavage), individually. Serum level of TNF-α was measured using specific ELISA kits. MMP2 and MMP9 contents were measured using Gelatin Zymography method. Brain samples were collected for histopathological and morphological examinations. Results: Arsenic treatment induced white matter lesions and cellular damages at hippocampal CA1 area of the brain. The number of hippocampal CA1 pyramidal cells was significantly declined in arsenic exposed rats (p<0.05). Treatment with NAC and Cur improved these abnormalities. The mean levels of MMP2, MMP9 and TNF-α inflammatory biomarkers were slightly declined after treatment with NAC and Cur (p>0.05). Conclusion: NAC and Cur play an important role in protecting the hippocampal CA1 cells injury induced by arsenic.