Oxidative stress and matrix metalloproteinase-9 in acute ischemic stroke: the Biomarker Evaluation for Antioxidant Therapies in Stroke (BEAT-Stroke) study.
OBJECTIVE
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.
Neurovascular Clinical Science Unit, Mater University Hospital and University College Dublin, Ireland. pjkelly@partners.org
Peter J
PJ
Kelly
Jason D
JD
Morrow
MingMing
M
Ning
Walter
W
Koroshetz
Eng H
EH
Lo
Erin
E
Terry
Ginger L
GL
Milne
Jane
J
Hubbard
Hang
H
Lee
Elizabeth
E
Stevenson
Megan
M
Lederer
Karen L
KL
Furie
D000368:Aged; D000369:Aged, 80 and over; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D002545:Brain Ischemia / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology; D016022:Case-Control Studies; D002544:Cerebral Infarction / Q000473:pathology; D038524:Diffusion Magnetic Resonance Imaging; D028441:F2-Isoprostanes / Q000097:blood*; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology*; D012720:Severity of Illness Index; D020521:Stroke / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D016896:Treatment Outcome; D024502:alpha-Tocopherol / Q000494:pharmacology
D000975:Antioxidants; D015415:Biomarkers; D028441:F2-Isoprostanes; D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9; D024502:alpha-Tocopherol; D001205:Ascorbic Acid