Abstract
Edaravone, a potent free radical scavenger, is clinically used for the treatment of cerebral infarction in Japan. Here, we examined the effects of edaravone on the dynamics of high-mobility group box-1 (HMGB1), which is a key mediator of ischemic-induced brain damage, during a 48-h postischemia/reperfusion period in rats and in oxygen-glucose-deprived (OGD) PC12 cells. HMGB1 immunoreactivity was observed in both the cytoplasm and the periphery of cells in the cerebral infarction area 2 h after reperfusion. Intravenous administration of 3 and 6 mg/kg edaravone significantly inhibited nuclear translocation and HMGB1 release in the penumbra area and caused a 26.5 ± 10.4 and 43.8 ± 0.5% reduction, respectively, of the total infarct area at 24 h after reperfusion. Moreover, edaravone also decreased plasma HMGB1 levels. In vitro, edaravone dose-dependently (1–10 μM) suppressed OGD- and H2O2-induced HMGB1 release in PC12 cells. Furthermore, edaravone (3–30 μM) blocked HMGB1-triggered apoptosis in PC12 cells. Our findings suggest a novel neuroprotective mechanism for edaravone that abrogates the release of HMGB1.
Footnotes
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This work was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan; by Grants-in-Aid 17100007 (to S.T.) and 21390483 (to K.Ka.); and by a Health and Labor Sciences Research grant from the Ministry of Health, Labor and Welfare (to I.M.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.149484.
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ABBREVIATIONS: NXY-059, disodium 2,4disulfophenyl-N-tert-butyl nitrone; ·OH, hydroxyl radical(s); HMGB1, high-mobility group box-1; LPS, lipopolysaccharide; ROS, reactive oxygen species; OGD, oxygen-glucose deprivation; MAP, mitogen-activated protein; p-, phosphorylated; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene; MABP, mean tail arterial blood pressure; CBF, cerebral blood flow; rCBF, regional cerebral blood flow; MCAO, occlusion of the middle cerebral artery; TTC, 2,3,5-triphenyl tetrazolium chloride; ELISA, enzyme-linked immunosorbent assay; PBS, phosphate-buffered saline; PBST, phosphate-buffered saline/0.02% Tween 20; TBST, Tris-buffered saline/Tween 20; MTT, 3-(4,5-dimethylthiazolyl-2)-2,5 diphenyltetrazolium bromide; RAGE, receptor for advanced glycation end products.
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The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material. - Received December 6, 2008.
- Accepted March 16, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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