The Free Radical Scavenger Edaravone Rescues Rats from Cerebral Infarction by Attenuating the Release of High-Mobility Group Box-1 in Neuronal Cells

  1. Kiyoshi Kikuchi,
  2. Ko-ichi Kawahara,
  3. Salunya Tancharoen,
  4. Fumiyo Matsuda,
  5. Yoko Morimoto,
  6. Takashi Ito,
  7. Kamal Krishna Biswas,
  8. Kazunori Takenouchi,
  9. Naoki Miura,
  10. Yoko Oyama,
  11. Yuko Nawa,
  12. Noboru Arimura,
  13. Masahiro Iwata,
  14. Yutaka Tajima,
  15. Terukazu Kuramoto,
  16. Kenji Nakayama,
  17. Minoru Shigemori,
  18. Yoshihiro Yoshida,
  19. Teruto Hashiguchi and
  20. Ikuro Maruyama
  1. Division of Laboratory and Vascular Medicine, Field of Cardiovascular and Respiratory Disorders, Departments of Advanced Therapeutics (K.Ki., K.Ka., T.I., K.K.B., K.T., Y.O., Y.N., N.A., T.H., I.M.), Periodontology (Y.M.), and Dermatology (M.I.), Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan; Department of Pharmacology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand (S.T.); Division of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima University, Kagoshima, Japan (F.M., Y.Y.); Laboratory of Veterinary Diagnostic Imaging, Department of Veterinary Medicine, Faculty of Agriculture, Kagoshima University, Kagoshima, Japan (N.M.); Department of Neurosurgery, Omuta City General Hospital, Omuta, Japan (K.Ki., Y.T., T.K., K.N.); and Department of Neurosurgery, Faculty of Medicine, Kurume University, Kurume, Japan (M.S.)
  1. Address correspondence to:
    Dr. Ikuro Maruyama, Division of Laboratory and Vascular Medicine, Field of Cardiovascular and Respiratory Disorders, Department of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Science, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. E-mail: rinken{at}m3.kufm.kagoshima-u.ac.jp

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

  • 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.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.108.149484.

  • 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.

  • ↵Graphic The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

    • Received December 6, 2008.
    • Accepted March 16, 2009.
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  1. Published online before print March 17, 2009, doi: 10.1124/jpet.108.149484 JPET June 2009 vol. 329 no. 3 865-874
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