Development of antibody therapy for brain infarction

• Project/Area Number: 19590534
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Okayama University
• Principal Investigator: RYU Katsuyaku Okayama University, 大学院・医歯薬学総合研究科, 助教 (40432637)
• Co-Investigator(Kenkyū-buntansha): NISHIBORI Masahiro 岡山大学, 大学院・医歯薬学総合研究科, 教授 (50135943)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2007: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 脳梗塞 / 抗体治療 / ミクログリア / 血液脳関門

Research Abstract

わが国では、脳血管障害は死因上位を占め、有効な治療法開発が望まれて久しい現状である。申請者らは、起炎性の新規活性物質HMGB1に注目し、特異的抗HMGB1単クローン抗体の治療法を開発した。ラット中大脳動脈2時間閉塞再灌流の脳梗塞モデルを用いて、単クローン抗体の治療効果及びメカニズムを検討した。その結果、抗HMGB1単クローン抗体の末梢投与は脳梗塞巣を縮小し、運動麻痺症状を改善し、脳浮腫の進行を止めることが示唆された。虚血側の特定の視床下部領域、特にストレス応答に関連する脳部位で、HMGB1が発現誘導されていることが分かった。これらの知見は、虚血再灌流の脳障害に対する、抗HMGB1単クローン抗体の有効性を強く示唆する。

Research Products

• [Journal Article] Alleviation of ischemia-induced brain edema by activation of the central histaminergic system in rats (2008)
  • Author(s): Irisawa Y, Adachi N, Liu K, Arai T, Nagaro T
  • Journal Title: J Pharmacol Sci 108(1) Pages: 112-23
  • Peer Reviewed
• [Journal Article] Suppression of ischaemia-induced cytokine release by dimaprit and amelioration of liver injury in rats (2008)
  • Author(s): Motoki A, Adachi N, Liu K, Takahashi HK, Nishibori M, Yorozuya T, Arai T, Nagaro T
  • Journal Title: Basic Clin Pharmacol Toxicol 102(4) Pages: 394-8
  • Peer Reviewed
• [Journal Article] Effects of HMGB1 on ischemia reperfusion injury in the rat heart (2008)
  • Author(s): Oozawa S, Mori S, Kanke T, Takahashi H, Liu K, Tomono Y, Asanuma M, Miyazaki I, Nishibori M
  • Journal Title: Sano S Circ J 72(7) Pages: 1178-84
  • NAID: 110006792076
  • Peer Reviewed
• [Journal Article] Stimulation of adenosine A2A receptor inhibits LPS-induced expression of intercellular adhesion molecule 1 and production of TNF-alpha in human peripheral blood mononuclear cells (2008)
  • Author(s): Hamano R, Takahashi HK, Iwagaki H, Kanke T, Liu K, Yoshino T, Sendo T, Nishibori M, Tanaka N
  • Journal Title: Shock 29(2) Pages: 154-9
  • Peer Reviewed
• [Journal Article] Inducible histamine protects mice from hepatitis through H2-receptor stimulation (2008)
  • Author(s): Mori S, Takahashi HK, Nishibori M
  • Journal Title: Yakugaku Zasshi 128(2) Pages: 247-53
  • Peer Reviewed
• [Journal Article] ラット中脳動脈閉塞・再灌流モデルにおける抗HMGB1単クローン抗体の治療効果 (2008)
  • Author(s): 劉克約、森秀治、高橋英夫、西堀正洋
  • Journal Title: 岡山医学会雑誌 第120巻第3号 Pages: 271-277
  • NAID: 130004903140
  • Peer Reviewed
• [Journal Article] Stimulation of adenosine A2A receptor inhibits LPS-induced expression of intercellular adhesion molecule 1 and production of TNF-alpha in human peripheral blood mononuclear cells. (2008)
  • Author(s): Hamano R
  • Journal Title: Shock 29 Pages: 154-159
  • Peer Reviewed
• [Journal Article] Effects of HMGB1 on ischemia-reperfusion injury in the rat heart. (2008)
  • Author(s): Oozawa S
  • Journal Title: Circ J. 72 Pages: 1178-1184
  • Peer Reviewed
• [Journal Article] Recovery of brain dopamine metabolism by branched-chain amino acids in rats with acute hepatic failure (2007)
  • Author(s): Deshpande G, Adachi N, Liu K, Motoki A, Mitsuyo T, Nagaro T, Arai T
  • Journal Title: J Neurosurg Anesthesiol 19(4) Pages: 243-8
  • Peer Reviewed
• [Journal Article] Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats (2007)
  • Author(s): Liu K, Mori S, Takahashi HK, Tomono Y, Wake H, Kanke T, Sato Y, Hiraga N, Adachi N, Yoshino T, Nishibori M.
  • Journal Title: FASEB J 21(14) Pages: 3904-16
  • NAID: 130004903140
  • Peer Reviewed
• [Journal Article] Action profiles of statins and calcineurin inhibitors during human mixed lymphocyte reaction (2007)
  • Author(s): Takahashi HK, Iwagaki H, Yagi T, Kanke T, Liu K, Yoshino T, Tanaka N, Nishibori M
  • Journal Title: Clin Immunol 123(3) Pages: 324-32
  • Peer Reviewed
• [Journal Article] The immunosuppressive effects of nicotine during human mixed lymphocyte reaction (2007)
  • Author(s): Takahashi HK, Iwagaki H, Hamano R, Kanke T, Liu K, Sadamori H, Yagi T, Yoshino T, Tanaka N, Nishibori M
  • Journal Title: Eur J Pharmacol 559(1) Pages: 69-74
  • Peer Reviewed
• [Journal Article] Effect of amodiaquine, a histamine N-methyltransferase inhibitor, on, Propionibacterium acnes and lipopolysaccharide-induced hepatitis in mice (2007)
  • Author(s): Yokoyama A, Mori S, Takahashi HK, Kanke T, Wake H, Nishibori M
  • Journal Title: Eur J Pharmacol 558(1-3) Pages: 179-84
  • Peer Reviewed
• [Journal Article] Effect of adenosine receptor subtypes stimulation on mixed lymphocyte reaction (2007)
  • Author(s): Takahashi HK, Iwagaki H, Hamano R, Kanke T, Liu K, Sadamori H, Yagi T, Yoshino T, Sendo T, Tanaka N, Nishibor M
  • Journal Title: Eur J Pharmacol 564(1-3) Pages: 204-10
  • Peer Reviewed
• [Journal Article] Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats. (2007)
  • Author(s): Liu K, et. al.
  • Journal Title: FASEB Journal 21 Pages: 3904-3916
  • NAID: 130004903140
  • Peer Reviewed
• [Journal Article] The Effects of HMGB1 on Ischemia-Reperfusion Injury in the Rat Heart. (2007)
  • Author(s): Oozawa S
  • Journal Title: Circulation Journal (in press)
  • Peer Reviewed
• [Presentation] ラット中脳動脈閉塞・再灌流モデルにおけるBBBと抗HMGB1抗体の効果 (2009)
  • Author(s): 劉克約(他)
  • Organizer: 第81日本回薬理学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2009-03-18
• [Presentation] ラット中大脳動脈閉塞・再濯流モデルにおけるBBB破綻と抗HMGBl抗体の効果 (2009)
  • Author(s): 劉 克約
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2009-03-18
• [Presentation] ラット中脳動脈閉塞・再灌流モデルにおけるBBB破綻と抗HMGB1単クローン抗体の治療効果 (2008)
  • Author(s): 劉克約(他)
  • Organizer: 第113回日本薬理学会近畿部会
  • Place of Presentation: 岡山
  • Year and Date: 2008-06-20
• [Presentation] ラット中大脳動脈閉塞・再還流モデルにおけるBBBの破錠と抗HMGB1単クローン抗体の治療効果 (2008)
  • Author(s): 劉 克約
  • Organizer: 第113回日本薬理学会近畿部会
  • Place of Presentation: 岡山
  • Year and Date: 2008-06-20
• [Presentation] ラット中脳動脈閉塞・再灌流モデルにおける抗HMGB1単クローン抗体の治療効果 (2008)
  • Author(s): 劉克約(他)
  • Organizer: 第80回薬理学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2008-03-17
• [Presentation] ラット中脳動脈閉塞・再還流モデルにおける抗HMGB1単コローン抗体の治療効果 (2008)
  • Author(s): 劉 克約, 他
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2008-03-17
• [Presentation] A novel anti-inflammatory transient of acute brain infarction by anti-HMGB1 monoclonal antibody (2007)
  • Author(s): 西堀正洋(他)
  • Organizer: Neurocience Meeting
  • Place of Presentation: アメリカ サンディエゴ
  • Year and Date: 2007-11-08
• [Presentation] A novel anti-inflammatory transient of acute brain infarction by anti-HMGB1 monoclonal antibody (2007)
  • Author(s): 西堀 正洋, 他
  • Organizer: Neuroscience Meeting 2007
  • Place of Presentation: アメリカ サンディエゴ
  • Year and Date: 2007-11-08