Reza Forghani MD, PhD, Presenter: Stockholder, Real-Time Radiology, Inc

Gregory R. Wojtkiewicz MSC, Abstract Co-Author: Nothing to Disclose

Makoto Hayase, Abstract Co-Author: Nothing to Disclose

Yinian Zhang, Abstract Co-Author: Nothing to Disclose

Daniel Seeburg, Abstract Co-Author: Nothing to Disclose

Michael Moskowitz MD, Abstract Co-Author: Nothing to Disclose

Ralph Weissleder MD, PhD, Abstract Co-Author: Shareholder, VisEn Medical, Inc, Bedford, MA

John Chen MD, PhD, Abstract Co-Author: Nothing to Disclose

Inflammation correlates with adverse stroke outcome but the underlying molecular mechanisms and their impact on stroke outcome remain poorly understood. Myeloperoxidase (MPO) is an oxidative enzyme secreted in large amounts by macrophages and neutrophils following ischemic cerebral infarction. We investigated whether inhibition of MPO activity can reduce final infarct volume and used the molecular imaging agent bis-5 hydroxytryptamide-DTPA(Gd) (MPO-Gd) to monitor therapeutic modulation of the MPO inhibitor in vivo.

Right-sided cerebral ischemia was induced in C57BL6 mice using a model of transient ischemic injury consisting of thread occlusion of the right middle cerebral artery for 20 minutes followed by reperfusion. Mice were treated with the specific MPO inhibitor 4-aminobenzoic acid hydrazide (ABAH, n=10) or saline (controls, n=7) and followed for a total of 21 days using serial MR imaging performed on a 4.7T small animal MRI scanner (Bruker, Billerica, MA) with diffusion weighted images (days 1, 3), T2w images (days 1, 3, 7, 14, 21), and T1w images obtained before and after intravenous administration of MPO-Gd (days 1, 3, 7, 14, 21). Absolute infarct volumes and the ratio of final infarct volume on T2w images relative to the initial DWI abnormality were determined as final end-points of tissue damage/gliosis.

There was extensive MPO-Gd enhancement in the infarct bed in control mice that was greatest on days 3 and 7 with gradual reduction subsequently. MPO-Gd enhancement was reduced in ABAH-treated mice consistent with partial inhibition of MPO activity. There was significantly reduced absolute mean final infarct volume (day 21) in the ABAH group compared to controls (7.3 mm3 vs 15.3 mm3, p = 0.01). Likewise, the mean infarct ratio (corrected for initial infarct volume) was significantly reduced in the ABAH group compared to controls (12 % vs 28%, p = 0.001).

Modulation of MPO activity can be evaluated in vivo using MPO-Gd molecular imaging and partial MPO inhibition results in significantly reduced final infarct volume, likely by reducing secondary tissue damage from inflammation.

MPO, a downstream effector of the inflammatory cascade, is a potential therapeutic target for stroke therapy and its activity can be monitored non-invasively using MPO-Gd molecular imaging.

Forghani, R, Wojtkiewicz, G, Hayase, M, Zhang, Y, Seeburg, D, Moskowitz, M, Weissleder, R, Chen, J, Myeloperoxidase as an Imaging Biomarker and Therapeutic Target in the Murine Stroke Model.  Radiological Society of North America 2010 Scientific Assembly and Annual Meeting, November 28 - December 3, 2010 ,Chicago IL. http://archive.rsna.org/2010/9009705.html