Oxidative Stress and Matrix Metalloproteinase-9 in Acute Ischemic Stroke

Abstract

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 Ͻ8 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, Pϭ0.012). No difference in F2IPSs was present at later time points. Early plasma F2IPs correlated with MMP-9 in all patients (Pϭ0.01) and the tPA-treated subgroup (Pϭ0.02). No correlation was found with NIHSS, DWI infarct volume, 90-day Rankin score, or C-reactive protein (PϾ0.05 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. (Stroke. 2008;39:100-104.)

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

“…57 In humans, MMP-9 activity increases early, with a peak at 6 to 8 hours after stroke and a return toward baseline by 24 to 26 hours. 48 MMP-9 mRNA levels are also increased in human peripheral leukocytes at 3 and 5 hours after stroke with a return toward baseline by 24 hours 58,59 ( Figure 4). Thus, there appears to be a transient increase in MMP-9 levels in circulating leukocytes and plasma, with a peak between 2and 8 hours of ischemic stroke onset.…”

“…47 The rate of early HT and severity of BBB disruption are reduced in mice deficient in NOX2 and when NOX2 is inhibited. 47 In humans, the oxidative stress marker F2-isoprostane is increased in blood early after stroke onset (median 6 hours) 48 and plasma levels of 3-nitrotyrosine are elevated at 3 and 24 hours. 49 Indeed, several clinical factors associated with HT in stroke patients may promote the generation of ROS, including age, glucose, diabetes, infarct size, congestive heart failure, and renal impairment 50 ( Figure 3; Table 1).…”

Systematic review on the association between F2-isoprostanes and cardiovascular disease

“…Three studies reported higher levels of plasma F 2 -isoprostanes in ischaemic stroke patients as compared with healthy participants. 31,33,34 In contrast, one study reported that patients with aneurysmal subarachnoid hemorrhage had higher levels of free form of F 2 -isoprostanes after surgery in both plasma and cerebrospinal fluid as compared with controls. 32 Note that only one of the four included studies performed multivariable analysis to control confounding.…”

Korean red ginseng protects against neuronal damage induced by transient focal ischemia in rats

“…Reactive oxygen species (ROS) have been indicated as one of the earliest and most significant components of tissue injury following reperfusion of the ischemic organ (4,5). The brain is quite vulnerable to oxidative stress due to its high polyunsaturated fatty acid content, which is particularly susceptible to ROS damage (6,7).…”