Mechanism for HMGB-or HMGB1-derived peptide-induced increase in BBB permeability

• Project/Area Number: 21390071
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Okayama University
• Principal Investigator: NISHIBORI Masahiro 岡山大学, 大学院・医歯薬学総合研究科, 教授 (50135943)
• Co-Investigator(Kenkyū-buntansha): RYU Katsuyaku 岡山大学, 大学院・医歯薬学総合研究科, 助教 (40432637) ; WAKE Hidenori 岡山大学, 大学院・医歯薬学総合研究科, 助教 (60570520) ; TAKAHASHI Hideo 岡山大学, 大学院・医歯薬学総合研究科, 准教授 (60335627)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000); Fiscal Year 2011: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2010: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2009: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
• Keywords: HMGB1 / 脳血管透過性 / 脳浮腫

Research Abstract

A representative damage-associated molecular pattern, high mobility group box-1(HMGB1), was released from neuronal nuclei to extracellular space via cytosol after ischemia or traumatic brain injury. The released HMGB1 induced contractile response in vascular endothelial cells and pericytes leading to the increased permeability of BBB. Among HMGB1-derived peptides, some had plural activities. Anti-HMGB1 monoclonal antibody inhibited the BBB permeability and inflammatory responses induced by traumatic brain injury.

Research Products

• [Journal Article] Anti-high Mobility Group Box-1 Monoclonal Antibody Protects the Blood-Brain Barrier from Ischemia-Induced Disruption in Rats. (2011)
  • Author(s): Zhang J, Liu K, Wake H, Nishibori M. et al.(11名、11番目)
  • Journal Title: Stroke Volume: 42(5) Pages: 1420-1428
  • Peer Reviewed
• [Journal Article] High-Mobility Group Box Protein 1 Neutralization Reduces Development of Diet-Induced Atherosclerosis in Apolipoprotein E-Deficient Mice. (2011)
  • Author(s): Kanellakis P, Liu K, Nishibori M, et al.(11名、10番目) Bobik A.
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 31(2) Pages: 313-9
  • Peer Reviewed
• [Journal Article] Reduction of the infarct size by simultaneous administration of l-histidine and diphenhydramine in ischaemic rat brains. (2011)
  • Author(s): Adachi N, Liu K, Nishibori M., et al.(7名、7番目)
  • Journal Title: Resuscitation Volume: 82(2) Pages: 219-21
  • Peer Reviewed
• [Journal Article] Reduction of the infarct size by simultaneous administration of 1-histidine and diphenhydramine in ischaemic rat brains (2011)
  • Author(s): Adachi N
  • Journal Title: Resuscitation Volume: 82(2) Pages: 219-21
  • Peer Reviewed
• [Journal Article] High-Mobility Group Box Protein 1 Neutralization Reduces Development of Diet-Induced Atherosclerosis in Apolipoprotein E-Deficient Mice (2011)
  • Author(s): Kanellakis P
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 31(2) Pages: 313-9
  • Peer Reviewed
• [Journal Article] Anti-high Mobility Group Box-1 Monoclonal Antibody Protects the Blood-Brain Barrier fromIschemia-Induced Disruption in Rats (2011)
  • Author(s): Zhang J
  • Journal Title: Stroke Volume: 42(5) Pages: 1420-1428
  • Peer Reviewed
• [Journal Article] Ciprofloxacin inhibits advanced glycation end products-induced adhesion molecule expression on human monocytes. (2010)
  • Author(s): Mori S, Liu K, Wake H, Nishibori M., et al.(8名、8番目)
  • Journal Title: Br J Pharmacol Volume: 161 Pages: 229-40
  • Peer Reviewed
• [Journal Article] Histamine inhibits adhesion molecule expression in human monocytes, induced by advanced glycation end products, during the mixed lymphocyte reaction. (2010)
  • Author(s): Zhang J, Liu K, Wake H, Nishibori M., et al.(11名、11番目)
  • Journal Title: Br J Pharmacol Volume: 160 Pages: 1378-86
  • Peer Reviewed
• [Journal Article] Prostaglandin E2 inhibits advanced glycation end product-induced adhesion molecule expression on monocytes, cytokine production, and lymphocyte proliferation during human mixed lymphocyte reaction. (2010)
  • Author(s): Takahashi HK, Liu K, Wake H, Nishibori M., et al.(11名、11番目)
  • Journal Title: J Pharmacol Exp Ther Volume: 334 Pages: 964-72
  • Peer Reviewed
• [Journal Article] Effect of nicotine on advanced glycation end product-induced immune response in human monocytes (2010)
  • Author(s): Takahashi HK, Liu K, Wake H, Nishibori M, et al., (8名、8番目)
  • Journal Title: J Pharmacol Exp Ther Volume: 332 Pages: 1013-1021
  • Peer Reviewed
• [Journal Article] Advanced glycation end products enhance monocyte activation during human mixed lymphocyte reaction. (2010)
  • Author(s): Ohashi K, Liu K, Wake H, Nishibori M, et al., (11名、10番目)
  • Journal Title: Clin Immunol Volume: 134 Pages: 345-353
  • Peer Reviewed
• [Journal Article] β2-adrenoceptor stimulation inhibits advanced glycation end products-induced adhesion molecule expression and cytokine production in human peripheralblood mononuclear cells. (2010)
  • Author(s): Takahashi HK
  • Journal Title: Eur J Pharmacol Volume: 627 Pages: 313-317
  • Peer Reviewed
• [Journal Article] Effect of nicotine on advanced glycation end products-induced immune response in human monocytes (2010)
  • Author(s): Takahashi HK
  • Journal Title: J Pharmacol Exp Ther Volume: 332 Pages: 1013-1021
  • Peer Reviewed
• [Journal Article] Prostaglandin E2 inhibits advanced glycation end product-induced adhesion molecule expression on monocytes, cytokine production, and lymphocyte proliferation during human mixed lymphocyte reaction (2010)
  • Author(s): Takahashi HK
  • Journal Title: J Pharmacol Exp Ther Volume: 334 Pages: 964-972
  • Peer Reviewed
• [Journal Article] Histamine inhibits adhesion molecule expression in human monocytes, induced by advanced glycation end products, during the mixed lymphocyte reaction (2010)
  • Author(s): Zhang J
  • Journal Title: Br J Pharmacol Volume: 160 Pages: 1378-1386
  • Peer Reviewed
• [Journal Article] Ciprofloxacin inhibits advanced glycation end products-induced adhesion molecule expression on human monocytes (2010)
  • Author(s): Mori S
  • Journal Title: Br J Pharmacol Volume: 161 Pages: 229-240
  • Peer Reviewed
• [Journal Article] Prostaglandins E2 inhibits advanced glycation end products-induced adhesion molecule expression, cytokine production and lymphocyte proliferation in human peripheral blood mononuclear cells (2009)
  • Author(s): Takahashi HK, Liu K, Wake H, Nishibori M, et al., (8名、8番目)
  • Journal Title: J Pharmacol Exp Ther Volume: 331 Pages: 656-670
  • Peer Reviewed
• [Journal Article] Histamine inhibits advanced glycation end products-induced adhesion molecule expression on human monocytes. (2009)
  • Author(s): Wake H, Takahashi HK, Liu K, Nishibori M, et al., (6名、6番目)
  • Journal Title: J. Pharmacol Exp Ther Volume: 330 Pages: 826-33
  • Peer Reviewed
• [Journal Article] Advanced glycation end products subspecies-selectively induce adhesion molecule expression and cytokine production in human peripheral blood mononuclear cells. (2009)
  • Author(s): Takahashi HK, Wake H, Liu K, Nishibori M, et al., (10名、10番目)
  • Journal Title: J Pharmacol Exp Ther Volume: 330 Pages: 89-98
  • Peer Reviewed
• [Journal Article] Prostaglandin E2 inhibits advanced glycation end product-induced adhesion molecule expression, cytokine production, and lymphocyte proliferation in human peripheral blood mononuclear cells. (2009)
  • Author(s): Takahashi HK
  • Journal Title: J Pharmacol Exp Ther. 331 Pages: 656-670
  • Peer Reviewed
• [Journal Article] Histamine inhibits advanced glycation end products-induced adhesion molecule expression on human monocytes. (2009)
  • Author(s): Wake H
  • Journal Title: J Pharmacol Exp Ther. 330 Pages: 826-830
  • Peer Reviewed
• [Journal Article] Advanced glycation end products subspecies-selectively induce adhesion molecule expression and cytokine production in human peripheral blood mononuclear cells. (2009)
  • Author(s): Takahashi HK
  • Journal Title: J Pharmacol Exp Ther. 330 Pages: 89-98
  • Peer Reviewed
• [Journal Article] Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain
  • Author(s): Shichida T., Nishibori M., et al.(18名、14番目)
  • Journal Title: Nature Medicine Volume: (in press)
  • Peer Reviewed
• [Journal Article] Anti-High Mobility Group Box-1 Antibody Therapy for Traumatic Brain Injury
  • Author(s): Okuma Y., Liu K., Wake H., Nishibori M., et al.(16名、16番目)
  • Journal Title: Annals of Neurology Volume: (in press)
  • NAID: 130004427993
  • Peer Reviewed
• [Journal Article] Anti-High Mobility Group Box-1 Antibody Therapy for Traumatic Brain Injury
  • Author(s): Okuma, Y
  • Journal Title: Annals of Neurology Volume: (in press)
  • Peer Reviewed
• [Journal Article] Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain
  • Author(s): Shichida, T
  • Journal Title: Nature Medicine Volume: (in press)
  • Peer Reviewed
• [Presentation] 炎症性サイトカインHMGB1をターゲットにした新規脳梗塞治療抗体-抗体治療の展開 (2012)
  • Author(s): 西堀正洋
  • Organizer: 平成23年度バイオビジネスアワードJAPAN
  • Place of Presentation: 大阪産業創造館4F
  • Year and Date: 2012-02-17
• [Presentation] 抗HMGB1単クローン抗体による虚血性脳障害の治療 (2011)
  • Author(s): 西堀正洋
  • Organizer: 第12回日本分子脳神経外科学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2011-10-14
• [Presentation] 抗HMGB1単クローン抗体はラット脳虚血による血液-脳関門の破錠を制御する (2011)
  • Author(s): 西堀正洋
  • Organizer: 第34回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2011-09-17
• [Presentation] Anti-HMGB1 monoclonal antibody protects BBB from ischemia-induced disruption in rats (2011)
  • Author(s): 西堀正洋
  • Organizer: 第34回日本神経科学大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2011-09-17
• [Presentation] 抗HMGB1単クローン抗体によるラットMCAO誘発脳梗塞の治療 (2011)
  • Author(s): 西堀正洋
  • Organizer: 第47回高血圧関連疾患モデル学会学術総会
  • Place of Presentation: 北海道大学学術交流会館
  • Year and Date: 2011-09-06
• [Presentation] 抗体医薬による血管疾患治療と創薬プラットホーム (2011)
  • Author(s): 西堀正洋
  • Organizer: 岡山脳研究セミナー
  • Place of Presentation: 岡山大学医学部記念会館2F
  • Year and Date: 2011-06-25
• [Presentation] 脳虚血早期におけるHMGB1の動態 (2011)
  • Author(s): 劉克約, 西堀正洋, 他4名
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: 神奈川,パシフィコ横浜
  • Year and Date: 2011-03-22
• [Presentation] Early translocation and release of HMGB1 in ischemic brain in rats (2011)
  • Author(s): 劉克約, 張継勇, 和氣秀徳, 高橋英夫, 森秀治, 西堀正洋
  • Organizer: 第84回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2011-03-22
• [Presentation] 脳虚血早期におけるHMGB1の動態 (2010)
  • Author(s): 劉克約, 張継勇, 和氣秀徳, 高橋英夫, 森秀治, 西堀正洋
  • Organizer: 第118回日本薬理学会近畿部会
  • Place of Presentation: 千里ライフサイエンスセンター
  • Year and Date: 2010-11-19
• [Presentation] 移植術後糖尿病に対するヒスタミンの効果の基礎検討 (2010)
  • Author(s): 高橋英夫, 劉克約, 和氣秀徳, 森秀治, 西堀正洋
  • Organizer: 第14回日本ヒスタミン学会
  • Place of Presentation: 川崎グランドホテル
  • Year and Date: 2010-10-24
• [Presentation] Anti-high mobility group box1 monoclonal antibody protects blood-brain barrier from ischemic insult in rat (2010)
  • Author(s): Liu K
  • Organizer: 14^<th> International Congress Of Immunology
  • Place of Presentation: Kobe International Exhibition Hall
  • Year and Date: 2010-08-26
• [Presentation] Disruption of BBB in rat MCAO and a protective effect of anti-HMGB1 antibody (2010)
  • Author(s): Liu K, Nishibori M
  • Organizer: 16^<th> World Congress on Basic and Clinical Pharmacology
  • Place of Presentation: Bella Center Copenhagen, Denmark
  • Year and Date: 2010-07-19
• [Presentation] Histamine inhibits advanced glycation end product-induced adhesion molecule expression on monocytes during human mixed lymphocyte reaction. (2010)
  • Author(s): 張継勇, 高橋英夫, 劉克約, 和氣秀徳, 劉瑞, 森秀治, 西堀正洋
  • Organizer: 第117回日本薬理学会近畿部会
  • Place of Presentation: 徳島県郷土文化会館
  • Year and Date: 2010-07-08
• [Presentation] A novel anti-HMGB1 treatment for brain infarction : protection of BBB disruption (2010)
  • Author(s): Nishibori M, 他10名
  • Organizer: The 4^<th> international HMGB1 symposium signals of tissue damage
  • Place of Presentation: Finland
  • Year and Date: 2010-06-23
• [Presentation] 抗体医薬による血管疾患治療と創薬プラットホーム構築 (2010)
  • Author(s): 西堀正洋
  • Organizer: 第130年会日本薬学会
  • Place of Presentation: 岡山コンベンションセンター他
  • Year and Date: 2010-03-30
• [Presentation] ラット中大脳動脈閉塞・再灌流モデルにおける抗HMGB1単クローン抗体の効果:脳血管透過性亢進に対する影響 (2010)
  • Author(s): 劉克約, 西堀正洋, 他6名
  • Organizer: 第83回日本薬理学会年会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2010-03-18
• [Presentation] A Proatherogenic Role for HMGB1 in Atherosclerosis (2009)
  • Author(s): Alex Bobik, Nishibori M, 他8名
  • Organizer: American Heart Association Meeting
  • Place of Presentation: Florida, USA
  • Year and Date: 2009-11-18
• [Presentation] 脳虚血時におけるHMGB1動態の初期変化 (2009)
  • Author(s): 西堀正洋, 他6名
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2009-09-17
• [Presentation] HMGB1を標的とした抗体医薬による脳梗塞の新規治療法 (2009)
  • Author(s): 西堀正洋
  • Organizer: 第8回国際バイオフォーラム
  • Place of Presentation: 東京ビックサイト
  • Year and Date: 2009-07-03
• [Remarks]
  • URL: http://www.cc.okayama-u.ac.jp/~pharmaco
• [Patent(Industrial Property Rights)] 外傷性神経障害治療剤 (2010)
  • Inventor(s): 西堀正洋他7名
  • Industrial Property Rights Holder: 西堀正洋他7名
  • Industrial Property Number: 2010-270133
  • Filing Date: 2010-12-03
• [Patent(Industrial Property Rights)] RAGEとAGEの結合抑制剤のスクリーニング方法 (2010)
  • Inventor(s): 西堀正洋他4名
  • Industrial Property Rights Holder: 西堀正洋他4名
  • Industrial Property Number: 2010-214019
  • Filing Date: 2010-09-24
• [Patent(Industrial Property Rights)] RAGEとAGEの結合抑制剤のスクリーニング方法 (2010)
  • Inventor(s): 西堀正洋、森秀治、高橋英夫、和氣秀徳、劉克約
  • Industrial Property Rights Holder: 国立大学法人岡山大学
  • Industrial Property Number: 2010-214019
  • Filing Date: 2010-09-24
• [Patent(Industrial Property Rights)] 外傷性神経障害治療剤 (2010)
  • Inventor(s): 西堀正洋、森秀治、高橋英夫、和氣秀徳、劉克約、伊達勲、大熊佑、友野靖子
  • Industrial Property Rights Holder: 国立大学法人岡山大学、医療法人創和会
  • Industrial Property Number: 2010-270133
  • Filing Date: 2010-12-03
• [Patent(Industrial Property Rights)] アテローム動脈硬化抑制剤 (2009)
  • Inventor(s): 西堀正洋他5名
  • Industrial Property Rights Holder: 西堀正洋他5名
  • Industrial Property Number: 2009-223472
  • Filing Date: 2009-09-28