title: Alpha-2 agonist attenuates ischemic injury in spinal cord neurons.
abstract: BACKGROUND
  Paraplegia secondary to spinal cord ischemia-reperfusion injury remains a devastating complication of thoracoabdominal aortic intervention. The complex interactions between injured neurons and activated leukocytes have limited the understanding of neuron-specific injury. We hypothesize that spinal cord neuron cell cultures subjected to oxygen-glucose deprivation (OGD) would simulate ischemia-reperfusion injury, which could be attenuated by specific alpha-2a agonism in an Akt-dependent fashion.
  
  
  METHODS
  Spinal cords from perinatal mice were harvested, and neurons cultured in vitro for 7-10 d. Cells were pretreated with 1 μM dexmedetomidine (Dex) and subjected to OGD in an anoxic chamber. Viability was determined by MTT assay. Deoxyuridine-triphosphate nick-end labeling staining and lactate dehydrogenase (LDH) assay were used for apoptosis and necrosis identification, respectively. Western blot was used for protein analysis.
  
  
  RESULTS
  Vehicle control cells were only 59% viable after 1 h of OGD. Pretreatment with Dex significantly preserves neuronal viability with 88% viable (P < 0.05). Dex significantly decreased apoptotic cells compared with that of vehicle control cells by 50% (P < 0.05). Necrosis was not significantly different between treatment groups. Mechanistically, Dex treatment significantly increased phosphorylated Akt (P < 0.05), but protective effects of Dex were eliminated by an alpha-2a antagonist or Akt inhibitor (P < 0.05).
  
  
  CONCLUSIONS
  Using a novel spinal cord neuron cell culture, OGD mimics neuronal metabolic derangement responsible for paraplegia after aortic surgery. Dex preserves neuronal viability and decreases apoptosis in an Akt-dependent fashion. Dex demonstrates clinical promise for reducing the risk of paraplegia after high-risk aortic surgery.
authors: Department of Surgery, University of Colorado, Denver, Colorado. Electronic address: kirsten.freeman@ucdenver.edu.
authors: Kirsten A
authors: KA
authors: Freeman
authors: Department of Anesthesiology, University of Colorado, Denver, Colorado.
authors: Ferenc
authors: F
authors: Puskas
authors: Department of Surgery, University of Colorado, Denver, Colorado.
authors: Marshall T
authors: MT
authors: Bell
authors: Department of Surgery, University of Colorado, Denver, Colorado.
authors: Joshua M
authors: JM
authors: Mares
authors: Department of Surgery, University of Colorado, Denver, Colorado.
authors: Lisa S
authors: LS
authors: Foley
authors: Department of Surgery, University of Colorado, Denver, Colorado.
authors: Michael J
authors: MJ
authors: Weyant
authors: Department of Surgery, University of Colorado, Denver, Colorado.
authors: Joseph C
authors: JC
authors: Cleveland
authors: Department of Surgery, University of Colorado, Denver, Colorado.
authors: David A
authors: DA
authors: Fullerton
authors: Department of Surgery, University of Colorado, Denver, Colorado.
authors: Xianzhong
authors: X
authors: Meng
authors: Department of Anesthesiology, University of Colorado, Denver, Colorado.
authors: Paco S
authors: PS
authors: Herson
authors: Department of Surgery, University of Colorado, Denver, Colorado.
authors: T Brett
authors: TB
authors: Reece
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis; D013504:Cardiovascular Surgical Procedures / Q000009:adverse effects*; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D020927:Dexmedetomidine / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control*; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000209:etiology / Q000517:prevention & control*
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D016207:Cytokines; D020927:Dexmedetomidine; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
keywords: Aortic surgery; Dexmedetomidine; Ischemia–reperfusion injury; Paraplegia