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.

CONCLUSION:

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: Mirko Pham, Xavier Helluy, Christoph Kleinschnitz, Peter Kraft, Andreas J Bartsch, Peter Jakob, Bernhard Nieswandt, Martin Bendszus, Guido Stoll
• Journal: PloS one (PLoS One) Vol. 6 Issue 4 Pg. e18386 (Apr 01 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21483769 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Immunoglobulin Fab Fragments
• Platelet Glycoprotein GPIb-IX Complex

Topics

• Animals
• Anti-Inflammatory Agents (immunology, pharmacology, therapeutic use)
• Cerebral Cortex (blood supply, drug effects)
• Cerebrovascular Circulation (drug effects)
• Disease Progression
• Immunoglobulin Fab Fragments (immunology, pharmacology, therapeutic use)
• Infarction, Middle Cerebral Artery (diagnosis, drug therapy, physiopathology)
• Magnetic Resonance Imaging
• Male
• Mice
• Platelet Glycoprotein GPIb-IX Complex (immunology)
• Time Factors