title: Dexmedetomidine, an α-2a adrenergic agonist, promotes ischemic tolerance in a murine model of spinal cord ischemia-reperfusion.
abstract: OBJECTIVE
  Dexmedetomidine, an α-2a adrenergic agonist, given pre- and postoperatively was previously shown to attenuate neuronal injury in a murine model of spinal cord ischemia-reperfusion. In the brain, α-2 agonists have been shown to induce the phosphorylation of cyclic AMP response-element binding protein (CREB), a transcription factor necessary for neuron survival. We hypothesized that the α-2a adrenergic agonist given preoperatively increases CREB-mediated neuroprotective proteins, attenuating neuronal injury and cytoarchitectural decay.
  
  
  METHODS
  Mice (ie, C57BL/6 mice) underwent 5 minutes of aortic occlusion via median sternotomy. Mice received 25 μg/kg dexmedetomidine or equivalent normal saline at 24 hours, 12 hours, and 30 minutes preoperatively. Functional outcomes were recorded at 6 to 48 hours postoperatively when spinal cords were removed for histologic analysis. Spinal cords were examined for protein kinase B, CREB, B-cell lymphoma 2, and brain-derived neurotrophic factor following treatment alone or ischemia-reperfusion surgery.
  
  
  RESULTS
  Following aortic occlusion, mice in the treatment group had preserved neurologic function at all time points (P < .05). Histologic analysis showed preserved cytoarchitecture and decreased neuronal injury in the treatment group when compared with ischemic controls. Additionally, analysis of spinal cord homogenate following surgery and pretreatment revealed a significant (P < .05) increase in B-cell lymphoma 2 and brain-derived neurotrophic factor expression and protein kinase B and CREB phosphorylation with α-2a adrenergic agonist pretreatment.
  
  
  CONCLUSIONS
  Pretreatment with the α-2a agonist dexmedetomidine preserved neurologic function and attenuated neuronal injury following thoracic aortic occlusion in mice. This relationship was associated with an increased phosphorylation of protein kinase B and CREB and subsequent up-regulation of antiapoptotic factor B-cell lymphoma 2 and brain-derived neurotrophic factor. Thus, α-2a receptor agonism-induced CREB phosphorylation and contributes to dexmedetomidine's protective mechanism in the spinal cord following ischemia.
authors.affiliation: Department of Surgery, School of Medicine, University of Colorado at Denver, Aurora, Colo. Electronic address: Marshall.bell@ucdenver.edu.
authors.forename: Marshall T
authors.initials: MT
authors.lastname: Bell
authors.affiliation: Department of Anesthesiology, School of Medicine, University of Colorado at Denver, Aurora, Colo.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Puskas
authors.affiliation: Department of Surgery, School of Medicine, University of Colorado at Denver, Aurora, Colo.
authors.forename: Daine T
authors.initials: DT
authors.lastname: Bennett
authors.affiliation: Department of Anesthesiology, School of Medicine, University of Colorado at Denver, Aurora, Colo.
authors.forename: Paco S
authors.initials: PS
authors.lastname: Herson
authors.affiliation: Department of Anesthesiology, School of Medicine, University of Colorado at Denver, Aurora, Colo.
authors.forename: Nidia
authors.initials: N
authors.lastname: Quillinan
authors.affiliation: Department of Surgery, School of Medicine, University of Colorado at Denver, Aurora, Colo.
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
authors.affiliation: Department of Surgery, School of Medicine, University of Colorado at Denver, Aurora, Colo.
authors.forename: T Brett
authors.initials: TB
authors.lastname: Reece
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000601:surgery; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D003250:Constriction; D020927:Dexmedetomidine / Q000494:pharmacology*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020760:Spinal Cord Ischemia / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D013997:Time Factors
chemical_list: C547769:Adra2a protein, mouse; D058647:Adrenergic alpha-2 Receptor Agonists; D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D018341:Receptors, Adrenergic, alpha-2; C052617:Bcl2 protein, mouse; D020927:Dexmedetomidine; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: 26.1; 38; 38.1; B-cell lymphoma 2; BCL-2; BDNF; CREB; IR; PBS; brain-derived neurotrophic factor; cyclic AMP response-element binding protein; ischemia-reperfusion; phosphate buffered saline