Effects of Edaravone, a Free Radical Scavenger, on Circulating Levels of MMP-9 and Hemorrhagic Transformation in Patients with Intravenous Thrombolysis Using Low-dose Alteplase

Abstract

Matrix metalloproteinase-9 (MMP-9) plays a key role for the blood-brain barrier disruption and intravenous tissue plasminogen activator (iv-tPA) therapy increases MMP-9. Edaravone, a free radical scavenger, reduces MMP-9-related blood-brain barrier disruption. We aimed to investigate whether edaravone would suppress the MMP-9 increase after iv-tPA using low-dose alteplase (0.6 mg/kg). Patients hospitalized within 12 hours after ischemic stroke onset between April 2008 and June 2013 were retrospectively examined. Patients with slight deficits (National Institutes of Health Stroke Scale score ≤ 4), stroke caused by arterial dissection, severe inflammatory disease or autoimmune disease, or regular use of steroid were excluded. Serum concentrations of high-sensitivity C-reactive protein, interleukin-6, MMP-2, and MMP-9 were serially measured at admission, after 24 hours, day 7, and day 14. General linear models were used to compare changes in concentrations of these biomarkers over time. A total of 63 patients (38 men, aged 74.48 ± 13.8 years) were studied. Patients were divided into 2 groups according to the iv-tPA therapy, that is, tPA group (n = 32) and non-tPA group (n = 31). Edaravone was administered routinely except for contraindication (90.6% in the tPA group and 87.1% in the non-tPA group). Significant interaction of group × time factor was observed only in MMP-9 concentrations by repeated-measure analysis of variance (P = .004). Association between iv-tPA therapy and subsequent hemorrhagic transformation was highly significant, but MMP-9 concentrations at any point did not predictive of subsequent hemorrhagic transformation (area under the receiver operating characteristic curve, .681). Low-dose iv-tPA increases MMP-9 concentration even in combination with Edaravone. The effect of higher dosage of Edaravone on circulating MMP-9 concentration and subsequent hemorrhagic transformation should be investigated.