Oxidative stress and matrix metalloproteinase-9 in acute ischemic stroke: the Biomarker Evaluation for Antioxidant Therapies in Stroke (BEAT-Stroke) study.

Kelly PJ, Morrow JD, Ning M, Koroshetz W, Lo EH, Terry E, Milne GL, Hubbard J, Lee H, Stevenson E, Lederer M, Furie KL
Stroke. 2008 39 (1): 100-4

PMID: 18063832 · DOI:10.1161/STROKEAHA.107.488189

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 0.0295 pg/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.

MeSH Terms (22)

Aged Aged, 80 and over alpha-Tocopherol Antioxidants Ascorbic Acid Biomarkers Brain Ischemia Case-Control Studies Cerebral Infarction Diffusion Magnetic Resonance Imaging F2-Isoprostanes Female Fibrinolytic Agents Humans Male Matrix Metalloproteinase 9 Middle Aged Oxidative Stress Severity of Illness Index Stroke Tissue Plasminogen Activator Treatment Outcome

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