on December 6, 2007
Published online before print December 6, 2007, doi: 10.1161/STROKEAHA.107.488189
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Submitted on March 14, 2007
From the Neurovascular Clinical Science Unit (P.J.K.), Mater University Hospital and University College Dublin, Ireland; Stroke Service, Department of Neurology (P.J.K., M.N., W.K., E.S., M.L., K.L.F.), Neuroprotection Research Laboratory, Departments of Neurology and Radiology (E.H.L.), and Bionutrition Service, Mallinckrodt General Clinical Resource Center (J.H.), and Biostatistics Center (H.L.), Massachusetts General Hospital and Harvard Medical School, Boston; and the Department of Medicine and Pharmacology (J.D.M., E.T., G.L.M.), Vanderbilt University School of Medicine, Nashville, Tenn. * To whom correspondence should be addressed. E-mail: pjkelly{at}partners.org.
Background and Purpose—Experimental stroke studies indicate that oxidative stress is a major contributing factor to ischemic cerebral injury. Oxidative stress is also implicated in activation of matrix metalloproteinases (MMPs) and blood-brain barrier injury after ischemia-reperfusion. Plasma biomarkers of oxidative stress may have utility as early indicators of efficacy in Phase 2 trials of antioxidant therapies in human stroke. To date, a valid biomarker has been unavailable. We measured F2-isoprostanes (F2IPs), free-radical induced products of neuronal arachadonic acid peroxidation, in acute ischemic stroke. We aimed to determine the change in plasma F2IP levels over time and relationship with plasma MMP-9 in tPA-treated and tPA-untreated stroke patients. Methods—We performed a case–control study of consecutive ischemic stroke patients (25 tPA-treated and 27 tPA-untreated) presenting within 8 hours of stroke onset. Controls were individuals without prior stroke from a primary care clinic network serving the source population from which cases were derived. Infarct volume was determined on acute diffusion-weighted MRI (DWI) performed within 48 hours using a semi-automated computerized segmentation algorithm. Phlebotomy was performed at <8 hours, 24 hours, 2 to 5 days, and 4 to 6 weeks. F2IPs were measured by gas chromatography/mass spectrometry and MMP-9 by ELISA. Prestroke antioxidant dietary intake was measured by the 24-hour recall method. Results—In 52 cases and 27 controls, early (median 6 hours postonset) F2IPs were elevated in stroke cases compared with controls (medians 0. 041 versus 0.0295pg/mL, P=0.012). No difference in F2IPSs was present at later time points. Early plasma F2IPs correlated with MMP-9 in all patients (P=0.01) and the tPA-treated subgroup (P=0.02). No correlation was found with NIHSS, DWI infarct volume, 90-day Rankin score, or C-reactive protein (P>0.05 for all). Conclusions—In early human stroke we found evidence of increased oxidative stress and a relationship with MMP-9 expression, supporting findings from experimental studies.
Revised on May 15, 2007
Accepted on June 8, 2007
Oxidative Stress and Matrix Metalloproteinase-9 in Acute Ischemic Stroke. The Biomarker Evaluation for Antioxidant Therapies in Stroke (BEAT-Stroke) Study
Peter J. Kelly MD, MS, FRCPI*;
Key words: cerebrovascular disorders • metalloproteinase • oxidative stress