title: Sustained reperfusion after blockade of glycoprotein-receptor-Ib in focal cerebral ischemia: an MRI study at 17.6 Tesla.
abstract: BACKGROUND
  Inhibition of early platelet adhesion by blockade of glycoprotein-IB (GPIb) protects mice from ischemic stroke. To elucidate underlying mechanisms in-vivo, infarct development was followed by ultra-high field MRI at 17.6 Tesla.
  
  
  METHODS
  Cerebral infarction was induced by transient-middle-cerebral-artery-occlusion (tMCAO) for 1 hour in C57/BL6 control mice (N = 10) and mice treated with 100 µg Fab-fragments of the GPIb blocking antibody p0p/B 1 h after tMCAO (N = 10). To control for the effect of reperfusion, additional mice underwent permanent occlusion and received anti-GPIb treatment (N = 6; pMCAO) or remained without treatment (N = 3; pMCAO). MRI 2 h and 24 h after MCAO measured cerebral-blood-flow (CBF) by continuous arterial-spin labelling, the apparent-diffusion-coefficient (ADC), quantitative-T2 and T2-weighted imaging. All images were registered to a standard mouse brain MRI atlas and statistically analysed voxel-wise, and by cortico-subcortical ROI analysis.
  
  
  RESULTS
  Anti-GPIb treatment led to a relative increase of postischemic CBF vs. controls in the cortical territory of the MCA (2 h: 44.2±6.9 ml/100 g/min versus 24 h: 60.5±8.4; p = 0.0012, F((1,18)) = 14.63) after tMCAO. Subcortical CBF 2 h after tMCAO was higher in anti-GPIb treated animals (45.3±5.9 vs. controls: 33.6±4.3; p = 0.04). In both regions, CBF findings were clearly related to a lower probability of infarction (Cortex/Subcortex of treated group: 35%/65% vs. controls: 95%/100%) and improved quantitative-T2 and ADC. After pMCAO, anti-GPIb treated mice developed similar infarcts preceded by severe irreversible hypoperfusion as controls after tMCAO indicating dependency of stroke protection on reperfusion.
  
  
  CONCLUSIONS
  Blockade of platelet adhesion by anti-GPIb-Fab-fragments results in substantially improved CBF early during reperfusion. This finding was in exact spatial correspondence with the prevention of cerebral infarction and indicates in-vivo an increased patency of the microcirculation. Thus, progression of infarction during early ischemia and reperfusion can be mitigated by anti-platelet treatment.
authors.affiliation: Department of Neuroradiology, University of Heidelberg, Heidelberg, Germany. mirko.pham@med.uni-heidelberg.de
authors.forename: Mirko
authors.initials: M
authors.lastname: Pham
authors.forename: Xavier
authors.initials: X
authors.lastname: Helluy
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Bartsch
authors.forename: Peter
authors.initials: P
authors.lastname: Jakob
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.forename: Martin
authors.initials: M
authors.lastname: Bendszus
authors.forename: Guido
authors.initials: G
authors.lastname: Stoll
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D018450:Disease Progression; D007140:Immunoglobulin Fab Fragments / Q000276:immunology* / Q000494:pharmacology* / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000175:diagnosis* / Q000188:drug therapy / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000276:immunology*; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D007140:Immunoglobulin Fab Fragments; D019038:Platelet Glycoprotein GPIb-IX Complex