Effects of dexmedetomidine on hippocampal focal adhesion kinase tyrosine phosphorylation in physiologic and ischemic conditions

被引:138
作者
Dahmani, S [1 ]
Rouelle, D [1 ]
Gressens, P [1 ]
Mantz, J [1 ]
机构
[1] Beaujon Univ Hosp, Dept Anesthesiol, F-92110 Clichy, France
关键词
D O I
10.1097/00000542-200511000-00011
中图分类号
R614 [麻醉学];
学科分类号
100217 ;
摘要
Background. Dexinedetomidine is a potent and selective alpha(2)-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 (antophosphorylated) 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. Methods: The effects of dexmedetomidine on phospho-tyrosine(397) 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 1h of reperfusion. FAK phosphorylation and caspase-3 activation were examined by immunoblotting. Neuronal death was assessed by propidium. iodide fluorescence. Results: Dexinedetomidine produced a dose-related increase in FAK phosphorylation (187 +/- 4%, mean SD, from basal level, EC50 = 0.2 mu m; 95% confidence interval, 0.09-0.5 mu M). This effect was stereorselective 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 bisindolyhnaleimide 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 mu m, 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 dexmdetomidine-induced reduction in caspase-3 expression was significantly decreased by the Src tyrosine kinase inhibitor PP2. Conclusion: Dexmedetomidine exhibits a preconditioning effect against ischemic injury in hippocampal slices subjected to wOGD. Increase in phosphorylation of FAK via stimulation of alpha(2) adrenoceptors and decrease in cleaved caspase-3 expression correlate with dexmedetomidine-induced cell survival.
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页码:969 / 977
页数:9
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