title: Preservation of motor function after spinal cord ischemia and reperfusion injury through microglial inhibition.
abstract: BACKGROUND
  Paraplegia remains a devastating complication of thoracoabdominal aortic procedures resulting from spinal cord ischemia and reperfusion injury (SCIR). Pharmacologic interventions have not proven efficacious in attenuating this injury, with poor understanding of the underlying mechanisms. The resident macrophages, or microglia in the spinal cord, may play a significant role in SCIR. The macrolide antibiotic, minocycline, has been shown in stroke models to inhibit microglial activation. This study hypothesized that microglial inhibition by minocycline after SCIR will attenuate injury with preservation of motor function.
  
  
  METHODS
  Mature male C57Bl/6 mice underwent 4 minutes of thoracic aortic occlusion with reperfusion. Mice receiving minocycline 30 minutes before ischemia and daily thereafter (90 mg/kg and 45 mg/kg, respectively) were compared with mice receiving vehicle controls. Hind-limb motor function was measured at 12-hour intervals, with spinal cord harvest for histologic and immunologic comparison at 60 hours.
  
  
  RESULTS
  Minocycline treatment significantly preserved hind limb motor function in all mice (n = 7) compared with complete paralysis in all untreated mice (n = 8), reaching significance from 24 hours of reperfusion through 60 hours. Immunofluorescent staining for Iba-1 revealed significant inhibition of microglial activation by minocycline treatment. Vehicle control sections demonstrated a greater degree of apoptosis compared with minocycline-treated spinal cord sections.
  
  
  CONCLUSIONS
  Minocycline limits microglial activation, paralleling functional preservation after aortic cross-clamping. These data suggest functional microglia contribute to reperfusion injury after spinal cord ischemia. The effects of minocycline demonstrate a potential pharmacological therapy as well as demonstrating a potential cellular target in preventing paraplegia after aortic intervention.
authors.affiliation: Department of Surgery, Division of Cardiothoracic Surgery, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. phillip.smith@ucdenver.edu
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Smith
authors.forename: Marshall T
authors.initials: MT
authors.lastname: Bell
authors.forename: Ferenc
authors.initials: F
authors.lastname: Puskas
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Cleveland
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Weyant
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
authors.forename: T Brett
authors.initials: TB
authors.lastname: Reece
mesh_terms: D000818:Animals; D007249:Inflammation / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000502:physiology*; D008911:Minocycline / Q000494:pharmacology; D009043:Motor Activity; D009410:Nerve Degeneration / Q000209:etiology; D015427:Reperfusion Injury / Q000503:physiopathology*; D020760:Spinal Cord Ischemia / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D014409:Tumor Necrosis Factor-alpha; D008911:Minocycline