Background: Dexmedetomidine has been reported to play an efficient role on multi-organ protection. Our study aims to investigate the neuroprotective of dexmedetomidine preconditioning on cerebral ischemic reperfusion (I/R) injury and investigate the underlining signaling mechanisms.;-;Methods: Cerebral I/R models were established with SD rats through middle cerebral artery occlusion (MCAO). After 2 h of ischemia followed by 7 days of reperfusion, the degree of cerebral tissue injury was detected by HE, Nissl and TUNEL staining. Glial fibrillary acidic protein (GFAP) positive and TNF-alpha positive cells were stained by immunohistochemistry and counted under microscope. TLR4, NF-kappa B and TIR-domain containing adapter-inducing interferon-beta (TRIF) expression were detected by real time PCR and western blot.;-;Results: Dexmedetomidine preconditioning markedly prevented the ischemia-induced cellular damage observed from HE and Nissl staining in hippocampus and cortex. Dexmedetomidine observably decreased the number of apoptotic cells in TUNEL staining. Besides, yohimbine could specifically suppress the protective effect of dexmedetomidine. GFAP expression was distinctly inhibited by dexmedetomidine preconditioning (10 mu g/kg, 20 mu g/kg) in cerebral ischemia area. Dexmedetomidine preconditioning inhibited the expression of TLR4 and NF-kappa B and increased that of TRIF.;-;Conclusion: The results of this study suggest that dexmedetomidine preconditioning plays a neuroprotective role against I/R injury. Dexmedetomidine might suppress TLR4/NF-??B pathway and drive TLR4/TRIF signaling pathway to reduce the inflammatory injury. (C) 2017 Elsevier Masson SAS. All rights reserved.