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Interferon regulatory factor 3 ( IRF3) is a transcription factor that plays a central role in the innate immune response, apoptosis, and oncogenesis. Previous studies have shown that endogenous IRF3 does not affect stroke in mice; however, paradoxically, elevated IRF3 expression was observed in the rat brains following cerebral ischemia/reperfusion (I/R) injury, indicating that IRF3 may have different functions during stroke in rats than in mice. A clear and comprehensive study of the effect of IRF3 on stroke in rats has been hampered by the lack of an IRF3-knockout rat strain. In this study, a novel IRF3 knockout rat strain and a transgenic rat strain with neuronal-specific IRF3 over-expression ( IRF3- TG) were created. Subsequently, the generated IRF3-knockout rats, the neuronal-specific IRF3 over-expressing rats and their corresponding controls were subjected to transient middle cerebral artery occlusion and followed by reperfusion, to investigate the exact role of IRF3 in cerebral I/R in rats. In contrast to the results in mice, IRF3 deficiency in rats provided significant protection against cerebral I/R injury and inhibited neuronal apoptosis, inflammation, and oxidative stress after cerebral I/R injury; the opposite patterns were observed in neuronal-specific IRF3 over-expressing rats. Taken together, these data demonstrate that IRF3 plays a negative regulatory role in cerebral I/R in rats, and IRF3 may be an attractive therapeutic target for preventing stroke. [ABSTRACT FROM AUTHOR]