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The Journal of Neuroscience, March 18, 2009, 29(11):3508-3517; doi:10.1523/JNEUROSCI.5332-08.2009

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Neurobiology of Disease
Diffusion-Weighted Magnetic Resonance Imaging Reversal by Gene Knockdown of Matrix Metalloproteinase-9 Activities in Live Animal Brains

Christina H. Liu,^1,2 Zerong You,³ Charng-Ming Liu,^1,2 Young R. Kim,² Michael J. Whalen,³ Bruce R. Rosen,² and Philip K. Liu^1,2

¹Laboratory for Transcript Targeting, Imaging and Repair, ²A. A. Martinos Center for Biomedical Imaging, Department of Radiology, and ³Department of Pediatrics, Massachusetts General Hospital, Charlestown, Massachusetts 02129

Correspondence should be addressed to Dr. Philip K. Liu, Department of Radiology, Massachusetts General Hospital, 149 13th Street, Room 2301, Charlestown, MA 02129. Email: philipl{at}nmr.mgh.harvard.edu

The involvement of matrix metalloproteinase-9 (MMP-9) activities in the development of abnormal water diffusion in the brain after cardiac arrest is not fully understood. We used magnetic resonance imaging to determine the correlation between MMP-9 activity and the mechanism of abnormal water diffusion after global cerebral ischemia (GCI)-induced brain damage in C57black6 mice. We induced GCI in mice by occluding both carotid arteries for 60 min, then allowing reperfusion. We labeled a short DNA that targets mmp-9 mRNA activity [phosphorothioate-modified oligodeoxynucleotide (sODN)-mmp9] or a control probe without intracellular target (sODN-Ran) with iron-based MR contrast agent [superparamagnetic iron oxide nanoparticle (SPION)-mmp9 or SPION-Ran] or fluorescein isothiocyanate (FITC)-sODN-mmp9 or FITC-sODN-Ran; we then delivered these probes by intracerebroventricular infusion or intraperitoneal injection within 3 h of reperfusion. At low dose (120 pmol/kg) the SPION-mmp9 probe was retained at significant levels in the striatum and cortex of living brains 10 h after GCI. Probe retention was validated by similar elevation of mmp-9 mRNA and antigens in postmortem samples taken from regions that exhibited GCI-induced hyperintensity in diffusion-weighted imaging, and a significant reduction in apparent diffusion coefficient (rADC, p = 0.0006, n = 12). At a higher dose (120 nmol/kg), the FITC-sODN-mmp9 probe revealed significant knockdown of MMP-9 activity, per zymography, and a reversal of striatal rADC (p = 0.004, n = 6). These observations were not duplicated in the control group. We conclude that expression of mmp-9 mRNA is associated with abnormal ADC after GCI.

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Received Nov. 5, 2008; revised Jan. 20, 2009; accepted Jan. 26, 2009.

Correspondence should be addressed to Dr. Philip K. Liu, Department of Radiology, Massachusetts General Hospital, 149 13th Street, Room 2301, Charlestown, MA 02129. Email: philipl{at}nmr.mgh.harvard.edu

This article has been cited by other articles:

				C. H. Liu, J. Q. Ren, J. Yang, C.-m. Liu, J. B. Mandeville, B. R. Rosen, P. G. Bhide, Y. Yanagawa, and P. K. Liu DNA-Based MRI Probes for Specific Detection of Chronic Exposure to Amphetamine in Living Brains J. Neurosci., August 26, 2009; 29(34): 10663 - 10670. [Abstract] [Full Text] [PDF]

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