Oxidative Stress and Matrix Metalloproteinase-9 in Acute Ischemic Stroke The Biomarker Evaluation for Antioxidant Therapies in Stroke (BEAT-Stroke) Study

Neurovascular Clinical Science Unit, Mater University Hospital and University College Dublin, Ireland.
Stroke (Impact Factor: 5.72). 01/2008; 39(1):100-4. DOI: 10.1161/STROKEAHA.107.488189
Source: PubMed


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.
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.
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).
In early human stroke we found evidence of increased oxidative stress and a relationship with MMP-9 expression, supporting findings from experimental studies.

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    • ", or by S-glutathiolation, S-nitrosylation, and phosphorylation reactions [23]. MMPs and oxidative stress seem to be strongly correlated in subjects with high cardiovascular risk [26] [27] [28] [29] [30] and this link has been demonstrated in several experimental models [31– 34]. Peroxynitrite (ONOO − ) activates some MMPs via the Sglutathiolation [31] [34] but, at higher concentrations, can lead to the inactivation of MMP-2 [34]. "
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    ABSTRACT: Our aim was to examine some parameters of oxidative status, gelatinases, and their inhibitors and to evaluate their interrelationships in subjects with metabolic syndrome (MS). We enrolled 65 MS subjects, subdivided according to the presence or not of diabetes mellitus. We examined lipid peroxidation (expressed as thiobarbituric acid reacting substances, TBARS), protein oxidation (expressed as carbonyl groups), nitric oxide metabolites (NO x ), total antioxidant status (TAS), MMP-2, MMP-9, TIMP-1, and TIMP-2. We found that MS subjects, diabetics and nondiabetics, showed an increase in TBARS, PC, and NO x . A significant decrease in TAS was observed only in nondiabetic MS subjects in comparison with diabetic MS subjects. We observed increased concentrations of MMP-2, MMP-9, TIMP-1, and TIMP-2, higher in diabetic subjects. Our data showed a positive correlation between TAS and MMP-2, TAS and MMP-9, and TAS and MMP-9/TIMP-1 and a negative correlation between TBARS and MMP-2 in diabetic MS subjects in the entire group. In MS subjects a prooxidant status and increased levels of gelatinases and their inhibitors are evident although the correlations between oxidative stress and MMPs or TIMPs are controversial and need further investigation.
    Mediators of Inflammation 07/2014; 2014:510619. DOI:10.1155/2014/510619 · 3.24 Impact Factor
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    • "Oxidative stress is involved in the pathophysiological mechanisms of stroke (e.g., atherosclerosis) and brain injury after ischemic stroke (e.g., reperfusion injury).1 Antioxidant levels and activities have been found to decrease after stroke as a consequence of increased oxidative stress, and thereafter increase gradually over time.2 "
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    ABSTRACT: Background and purpose: Oxidative stress is involved in the pathophysiological mechanisms of stroke (e.g., atherosclerosis) and brain injury after ischemic stroke. Statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, have both pleiotropic and low-density lipoprotein (LDL)-lowering properties. Recent trials have shown that high-dose statins reduce the risk of cerebrovascular events. However, there is a paucity of data regarding the changes in the oxidative stress markers in patients with atherosclerotic stroke after statin use. This study evaluated changes in oxidative stress markers after short-term use of a high-dose statin in patients with atherosclerotic stroke. Methods: Rosuvastatin was administered at a dose of 20 mg/day to 99 patients who had suffered an atherosclerotic stroke and no prior statin use. Blood samples were collected before and 1 month after dosing, and the serum levels of four oxidative stress markers-malondialdehyde (MDA), oxidized LDL (oxLDL), protein carbonyl content (PCO), and 8-hydroxy-2'-deoxyguanosine (8-OHdG)-were evaluated to determine the oxidation of MDA and lipids, proteins, and DNA, respectively, at both of those time points. Results: The baseline levels and the degrees of reduction after statin use differed among the oxidative stress markers measured. MDA and PCO levels were associated with infarct volumes on diffusion-weighted imaging (r=0.551, p<0.05, and r=0.444, p=0.05, respectively). Statin use decreased MDA and oxLDL levels (both p<0.05) but not the PCO or 8-OHdG level. While the reduction in MDA levels after statin use was not associated with changes in cholesterol, that in oxLDL levels was proportional to the reductions in cholesterol (r=0.479, p<0.01), LDL (r=0.459, p<0.01), and apolipoprotein B (r=0.444, p<0.05). Conclusions: The impact of individual oxidative stress markers differs with time after ischemic stroke, suggesting that different oxidative markers reflect different aspects of oxidative stress. In addition, short-term use of a statin exerts antioxidant effects against lipid peroxidation via lipid-lowering-dependent and -independent mechanisms, but not against protein or DNA oxidation in atherosclerotic stroke patients.
    Journal of Clinical Neurology 04/2014; 10(2):140-7. DOI:10.3988/jcn.2014.10.2.140 · 1.70 Impact Factor
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    • "The involvement of oxidative stress in the aetiology of stroke is well documented (Kontos 2001; S ¸ enes¸et al. 2007). Most studies have investigated the redox imbalance during the acute phase after a cerebrovascular eventS¸enes¸et al. 2007; Dominguez et al. 2010; Kelly et al. 2008; El Kossi and Zakhary 2000). Currently, there is a lack of information on the status of enzymatic and nonenzymatic antioxidant systems, as well as oxidative stress markers, in stroke patients during the postacute phase (Alexandrova and Bochev 2005; Manolescu et al. 2011). "
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    ABSTRACT: Stroke is a pathologic condition associated with redox imbalance. This pilot study was designed to evaluate the effect of the consumption of the nutritional supplement ALAnerv on some oxidative stress markers in postacute stroke patients undergoing rehabilitation. To achieve this goal, we assigned 28 patients to 2 study groups: (-)ALA and (+)ALA. Patients in both groups participated in the same rehabilitation program and received comparable standard medications; however, patients in the (+)ALA group received ALAnerv for 2 weeks (2 pills per day). We assessed total and nonproteic thiols, protein carbonyls, ceruloplasmin, oxidized low-density lipoprotein (LDL) particles, lipid hydroperoxide concentrations, gamma-glutamyl transpeptidase activity, and total antioxidant capacity. Regression analysis indicated that supplementation with ALAnerv was responsible for the significant decrease in glucose (p = 0.002) and oxidized LDL particles (p < 0.001) during the study period. For both parameters, the variation in the percent of concentration between the 2 groups during the study period reached statistical significance (p = 0.012 and p < 0.001, respectively). Moreover, Barthel Index values at discharge were significantly influenced by ALAnerv treatment. These preliminary results indicate that ALAnerv might be helpful because it rapidly corrects plasma fasting glucose and corrects serum oxidized LDL particle concentrations, suggesting the need for longer treatment with 2 pills or more per day.
    Applied Physiology Nutrition and Metabolism 06/2013; 38(6):613-620. DOI:10.1139/apnm-2012-0436 · 2.34 Impact Factor
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