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Dexmedetomidine is a potent and selective α2-adrenoceptor agonist that exhibits a broad pattern of actions, including sedation, analgesia, and neuroprotection. Some of these actions (e.g., neuroprotection) may require targets involved in long-term cellular changes. The authors hypothesized that dexmedetomidine increases the expression of active (autophosphorylated) focal adhesion kinase (FAK), a nonreceptor tyrosine kinase playing a pivotal role in cellular plasticity and survival. Therefore, we examined the cellular mechanisms involved in this effect and its sensitivity to oxygen-glucose deprivation (OGD) in rat hippocampal slices.The effects of dexmedetomidine on phospho-tyrosine397 FAK phosphorylation were studied first with or without various pharmacologic agents in normoxic conditions, and second in a model of pharmacologic preconditioning of slices subjected to 30 min of OGD followed by 1 h of reperfusion. FAK phosphorylation and caspase-3 activation were examined by immunoblotting. Neuronal death was assessed by propidium iodide fluorescence.Dexmedetomidine produced a dose-related increase in FAK phosphorylation (187 ± 4%, mean ± SD, from basal level, EC50 = 0.2 μm; 95% confidence interval, 0.09–0.5 μm). This effect was stereoselective and was completely blocked by yohimbine and the combination of the cyclic monophosphate permeant analog 8 bromo cyclic monophosphate and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. It was mimicked by the protein kinase A inhibitor H 89. In contrast, prazosin and the protein kinase C inhibitors chelerythrine and bisindolylmaleimide I were ineffective. OGD induced a significant increase in immunoreactivity of the cleaved caspase-3 17-kd fragment (417 ± 22; P < 0.001), a decrease in FAK phosphorylation (78 ± 12% of control; P < 0.05), and production of significant neuronal death. In OGD conditions, a preconditioning application of dexmedetomidine (0.2 μm, 20-min application, 3 h before anoxia) significantly reduced neuronal death and cleaved caspase-3 expression and significantly attenuated the decrease in phosphorylated FAK content. The dexmedetomidine-induced reduction in caspase-3 expression was significantly decreased by the Src tyrosine kinase inhibitor PP2.Dexmedetomidine exhibits a preconditioning effect against ischemic injury in hippocampal slices subjected to OGD. Increase in phosphorylation of FAK via stimulation of α2 adrenoceptors and decrease in cleaved caspase-3 expression correlate with dexmedetomidine-induced cell survival.