Characterization of the postconditioning effect of dexmedetomidine in mouse organotypic hippocampal slice cultures exposed to oxygen and glucose deprivation.
BACKGROUND
There is an increasing interest in the use of dexmedetomidine for anesthesia and sedation. Here, we used the mouse organotypic hippocampal slice culture to investigate whether dexmedetomidine exhibits postconditioning properties against oxygen and glucose deprivation (OGD). The role of the focal adhesion and extracellular-regulated kinases pathways in these effects were examined in both postconditioning and preconditioning.


METHODS
Slices were obtained from P5 mouse. In postconditioning experiments, Dexmedetomidine (1 microm) was incubated 60 min after the end of OGD. In preconditioning experiments, dexmedetomidine was applied 3 h before OGD. Pharmacologic modulation of the studied pathways was achieved by using selective inhibitors of these cascades. Cell death was assessed 72 h after OGD using propidium iodide labeling and protein expression of activated caspase 3.


RESULTS
Maximum cell death increased with the duration of OGD. Dexmedetomidine induced a postconditioning effect in the CA1 (but not dentate gyrus) subfield area, which was significantly reduced by modulators of the focal adhesion and the extracellular-regulated kinases pathways. The combination of the inhibitors of the two pathways completely abolished the postconditioning effect of dexmedetomidine. The preconditioning effect of dexmedetomidine against ischemia-induced injury was observed in all hippocampal subfield areas. Results obtained with the pharmacologic modulation used for postconditioning also applied to dexmedetomidine-induced preconditioning.


CONCLUSIONS
Dexmedetomidine exhibits significant, but moderate, postconditioning properties against oxygen and glucose deprivation-induced injury. Activation of focal adhesion and the imidazoline 1 receptors-extracellular-regulated kinases pathways is involved in dexmedetomidine-induced postconditioning and preconditioning as well.
Dahmani
Souhayl
S
Department of Anesthesia and Pain Management, INSERM U 676, Robert Debré University Hospital, Paris 7 Paris Diderot University, 48 Boulevard Sérurier, Paris, France. souhayl.dahmani@rdb.aphp.fr
Rouelle
Danielle
D
Gressens
Pierre
P
Mantz
Jean
J
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D020927:Dexmedetomidine / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D005947:Glucose / Q000172:deficiency*; D006624:Hippocampus / Q000187:drug effects*; D000860:Hypoxia / Q000473:pathology*; D054755:Imidazoline Receptors / Q000187:drug effects; D015151:Immunoblotting; D019194:Ischemic Preconditioning; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009924:Organ Culture Techniques; D010766:Phosphorylation; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D054755:Imidazoline Receptors; D018341:Receptors, Adrenergic, alpha-2; C410887:imidazoline I1 receptors; D020927:Dexmedetomidine; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053148:Caspase 3; D005947:Glucose