Therapeutic Potential of an Anti-High Mobility Group Box1 Monoclonal Antibody in Hemorrhagic stroke

• Project/Area Number: 16K08909
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Okayama University
• Principal Investigator: RYU katsuyaku 岡山大学, 医歯薬学総合研究科, 非常勤研究員 (40432637)
• Co-Investigator(Kenkyū-buntansha): 西堀 正洋 岡山大学, 医歯薬学総合研究科, 教授 (50135943)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 出血性脳卒中 / 血液脳関門 / 遅発性血管攣縮 / 抗体医薬 / HMGB1 / 脳内出血 / 硬膜下出血 / 脳血管攣縮 / 脳出血 / 硬膜外出血 / 薬物治療学

Outline of Final Research Achievements

High mobility group box1(HMGB1) originally identified as an architectural nuclear protein exhibits an inflammatory cytokine-like activity in the extracellular space. We showed that treatment with anti-HMGB1 monoclonal antibody (mAb) remarkably ameliorated delayed cerebral vasospasm and brain injury induced by cerebral hemorrhage　in rats, even when the mAb was administered after cerebral hemorrhage. Our results indicated that anti-HMGB1 mAb efficiently inhibited the development of delayed brain injury brain through the block HMGB1 translocation and protection of blood-brain barrier (BBB) structure in the cerebral hemorrhage region.

Academic Significance and Societal Importance of the Research Achievements

本研究では、出血性脳障害のメカニズムに、障害によって細胞内から放出されるタンパク質HMGB1が関与することを明らかにした。更に、出血性脳障害の早期における抗HMGB1抗体の優れた治療効果が確認された。出血性脳卒中は死亡率が高く、後遺症も重篤です。特にくも膜下出血を引き起こす遅発性血管攣縮が重大な後遺症の原因となることが多い。これまで、脳内出血による神経、血管障害を抑制する薬物は開発されておらず、抗HMGB1抗体による治療法は実用化に向けた研究が期待される。

Research Products

• [Journal Article] The C‐terminal region of tumor necrosis factor like weak inducer of apoptosis is required for interaction with advanced glycation end products (2018)
  • Author(s): Watanabe Masahiro、Toyomura Takao、Wake Hidenori、Liu Keyue、Teshigawara Kiyoshi、Takahashi Hideo、Nishibori Masahiro、Mori Shuji
  • Journal Title: Biotechnology and Applied Biochemistry Volume: 66 Issue: 2 Pages: 254-260
  • DOI: 10.1002/bab.1706
  • Peer Reviewed / Open Access
• [Journal Article] Histidine-Rich Glycoprotein Suppresses Hyperinflammatory Responses of Lung in a Severe Acute Pancreatitis Mouse Model (2018)
  • Author(s): Terao K, Wake H, Adachi N, Liu K, Teshigawara K, Takahashi H, Mori S, Nishibori M
  • Journal Title: Pancreas Volume: 47 Issue: 9 Pages: 1156-1164
  • DOI: 10.1097/mpa.0000000000001153
  • Peer Reviewed / Open Access
• [Journal Article] Inter-α inhibitor proteins maintain neutrophils in a resting state by regulating shape and reducing ROS production. (2018)
  • Author(s): Htwe SS, Wake H, Liu K, Teshigawara K, Stonestreet BS, Lim YP, Nishibori M.
  • Journal Title: Blood Adv. Volume: 2(15) Issue: 15 Pages: 1923-1934
  • DOI: 10.1182/bloodadvances.2018018986
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evidence of a role for spinal HMGB1 in ischemic stress-induced mechanical allodynia in mice. (2018)
  • Author(s): Matsuura W, Harada S, Liu K, Nishibori M, Tokuyama S.
  • Journal Title: Brain Res Volume: 15;1689 Pages: 1-10
  • DOI: 10.1016/j.brainres.2018.02.026
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic potential of an anti-high mobility group box-1 monoclonal antibody in epilepsy. (2017)
  • Author(s): Zhao J, Wang Y, Xu C, Liu K, Wang Y, Chen L, Wu X, Gao F, Guo Y, Zhu J, Wang S, Nishibori M, Chen Z.
  • Journal Title: Brain Behavior and Immunity Volume: 64 Pages: 308-319
  • DOI: 10.1016/j.bbi.2017.02.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Metformin Directly Binds the Alarmin HMGB1 and Inhibits its Proinflammatory Activity. (2017)
  • Author(s): Horiuchi T, Sakata N, Narumi Y, Kimura T, Hayashi T, Nagano K, Liu K, Nishibori M, Tsukita S, Yamada T, Katagiri H, Shirakawa R, Horiuchi H.
  • Journal Title: J Biol Chem. Volume: 印刷中 Issue: 20 Pages: 8436-8446
  • DOI: 10.1074/jbc.m116.769380
  • NAID: 120006331939
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Anti-high mobility group box-1 (HMGB1) antibody inhibits hemorrhage-induced brain injury and improved neurological deficits in rats. (2017)
  • Author(s): Wang D, Liu K, Wake H, Teshigawara K, Mori S, Nishibori M.
  • Journal Title: Sci Rep. Volume: 7:46243. Issue: 1 Pages: 46243-46243
  • DOI: 10.1038/srep46243
  • Peer Reviewed / Open Access
• [Journal Article] Therapeutic effects of anti-HMGB1 monoclonal antibody on pilocarpine-induced status epilepticus in mice. (2017)
  • Author(s): Fu L, Liu K, Wake H, Teshigawara K, Yoshino T, Takahashi H, Mori S, Nishibori M.
  • Journal Title: Sci Rep. Volume: 7(1):1179. Issue: 1 Pages: 1179-1179
  • DOI: 10.1038/s41598-017-01325-y
  • NAID: 130007901378
  • Peer Reviewed / Open Access
• [Journal Article] Advanced glycation end products attenuate the function of tumor necrosis factor-like weak inducer of apoptosis to regulate the inflammatory response (2017)
  • Author(s): Watanabe M, Toyomura T, Wake H, Liu K, Teshigawara K, Takahashi H, Nishibori M, Mori S
  • Journal Title: Molecular and Cellular Biochemistry Volume: 印刷中 Issue: 1-2 Pages: 153-162
  • DOI: 10.1007/s11010-017-3045-6
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Anti-high Mobility Group Box 1 Antibody Ameliorates Albuminuria in MRL/lpr Lupus-Prone Mice. (2017)
  • Author(s): Watanabe H, Watanabe KS, Liu K, Hiramatsu S, Zeggar S, Katsuyama E, Tatebe N, Akahoshi A, Takenaka F, Hanada T, Akehi M, Sasaki T, Sada KE, Matsuura E, Nishibori M, Wada J.
  • Journal Title: Molecular Therapy - Methods & Clinical Development Volume: 6 Pages: 31-39
  • DOI: 10.1016/j.omtm.2017.05.006
  • Peer Reviewed / Open Access
• [Journal Article] Macrophage-derived HMGB1 as a Pain Mediator in the Early Stage of Acute Pancreatitis in Mice: Targeting RAGE and CXCL12/CXCR4 Axis. (2017)
  • Author(s): Irie Y, Tsubota M, Ishikura H, Sekiguchi F, Terada Y, Tsujiuchi T, Liu K, Nishibori M, Kawabata A.
  • Journal Title: Journal of Neuroimmune Pharmacology Volume: 12 Issue: 4 Pages: 693-707
  • DOI: 10.1007/s11481-017-9757-2
  • Peer Reviewed / Open Access
• [Journal Article] The specific localization of advanced glycation end-products (AGEs) in rat pancreatic islets. (2017)
  • Author(s): Morioka Y, Teshigawara K, Tomono Y, Wang D, Izushi Y, Wake H, Liu K, Takahashi HK, Mori S, Nishibori M.
  • Journal Title: J Pharmacol Sci. Volume: 134(4) Issue: 4 Pages: 218-224
  • DOI: 10.1016/j.jphs.2017.07.005
  • Peer Reviewed / Open Access
• [Journal Article] Phagocytosis of Advanced Glycation End Products (AGEs) in Macrophages Induces Cell Apoptosis. (2017)
  • Author(s): Gao Y, Wake H, Morioka Y, Liu K, Teshigawara K, Shibuya M, Zhou J, Mori S, Takahashi H, Nishibori M.
  • Journal Title: Oxid Med Cell Longev. Volume: 2017:8419035 Issue: 1 Pages: 8419035-8419035
  • DOI: 10.1155/2017/8419035
  • Peer Reviewed / Open Access
• [Journal Article] Anti-high mobility group box-1 (HMGB1) antibody attenuates delayed cerebral vasospasm and brain injury after subarachnoid hemorrhage in rats (2016)
  • Author(s): Haruma J, Teshigawara K, Hishikawa T, Wang D, Liu K, Wake H, Mori S, Takahashi HK, Sugiu K, Date I, Nishibori M.
  • Journal Title: Scientific reports Volume: 6 Issue: 1 Pages: 37755-37768
  • DOI: 10.1038/srep37755
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of high mobility group box 1 in the development and maintenance of chemotherapy-induced peripheral neuropathy in rats (2016)
  • Author(s): Nishida, T., Tsubota, M., Kawaishi, Y., Yamanishi, H., Kawakami, N., Sekiguchi, F., Ishikura, H., Liu, K., Nishibori, M., Kawabata, A.
  • Journal Title: Toxocology Volume: 365 Pages: 48-58
  • DOI: 10.1016/j.tox.2016.07.016
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Possible involvement of the HMGB1/RAGE signaling mechanism in the induction of central post-stroke pain induced by acute global cerebral ischemia. (2016)
  • Author(s): Harada S, Matsuura W, Liu K, Nishibori M, Tokuyama S.
  • Journal Title: Brain Res. Volume: 1646 Pages: 433-440
  • DOI: 10.1016/j.brainres.2016.06.028
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] HMGB1 Translocation After Ischemia in the Ovine Fetal Brain. (2016)
  • Author(s): Zhang J, Klufas D, Manalo K, Adjepong K, Davidson JO, Wassink G, Bennet L, Gunn AJ, Stopa EG, Liu K, Nishibori M, Stonestreet BS.
  • Journal Title: J Neuropathol Exp Neurol. Volume: 75(6) Issue: 6 Pages: 527-538
  • DOI: 10.1093/jnen/nlw030
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Peripheral HMGB1-induced hyperalgesia in mice: redox state-dependent distinct roles of RAGE and TLR4 (2016)
  • Author(s): Yamasoba, D., Tsubota, M., Domoto, R., Sekiguchi, F., Nishikawa, H., Liu, K., Nishibori, M., Ishikura, H., Yamamoto, T., Taga, A., Kawabata, A.
  • Journal Title: J. Pharmacol. Sci. Volume: 130 Issue: 2 Pages: 139-142
  • DOI: 10.1016/j.jphs.2016.01.005
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Anti-high mobility group box-1 antibody therapy might prevent cognitive dysfunction after traumatic brain injury. (2018)
  • Author(s): Okuma Y, Liu K, Wake H, Teshigawara K, Mori S, Takahashi HK, Hirotsune N, Nishino S, Nishibori M.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] The analysis of anxiety-and depression-related behaviors in neuropathic pain of mice possible involvement of brain inflammation. (2018)
  • Author(s): Hisaoka-Nakashima K, Tomimura Y, Yoshii T, Zhang FF, Nakamura Y, Liu K, Nishibori M, Nakata Y, Morioka N.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] Therapeutic effects of anti-HMGB1 monoclonal antibody on pilocarpine-induced status epilepticus in mice. (2018)
  • Author(s): Nishibori M, Fu L, Wake H, Wang D, Teshigawara K, Liu K, Takahashi HK, Mori S.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] Specific action mediated by spinal HMGB1 receptors in the induction of central post-stroke pain. (2018)
  • Author(s): Matsuura W, Harada S, Liu K, Nishibori M, Tokuyama S.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] Anti-HMGB1 mAb therapy for intracerebral hemorrhage-induced brain injury in rats. (2018)
  • Author(s): Wang D, Liu K, Wake H, Teshigawara K, Mori S, Nishibori M.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] HMGB1 translocation induced by histamine in vascular endothelial cells in vitro (2018)
  • Author(s): Nishibori M, Gao S, Gao Y, Wake H, Liu K, Teshigawara K, Mori S.
  • Organizer: World Histamine Symposium
  • Int'l Joint Research
• [Presentation] 脊椎HMGB1関連受容体/グリア細胞/NOSシグナルを介する脳卒中後疼痛の発現機序の解明 (2018)
  • Author(s): 松浦渉、原田慎一、劉克約、西堀正洋、徳山尚吾
  • Organizer: 第138回日本薬理学会関東部会
• [Presentation] 脳卒中後疼痛に対する脊髄HMGB1およびその関連受容体の関与 (2018)
  • Author(s): 松浦歩、原田慎一、劉克約、西堀正洋、徳山尚吾
  • Organizer: 第133回日本薬理学会近畿部会
• [Presentation] 抗HMGB1抗体による脳内出血の治療 (2018)
  • Author(s): 王登莉、劉克約、和氣秀徳、勅使川原匡、森秀治、西堀正洋
  • Organizer: 第41回日本神経科学大会
• [Presentation] 炎症惹起因子HMGB1の糖代謝制御に対する生理的役割の検討 (2018)
  • Author(s): 兼森玄、勅使川原匡、劉克約、和氣秀徳、王登莉、髙橋英夫、森秀治、西堀正洋
  • Organizer: 第134回日本薬理学会近畿部会
• [Presentation] Anti-HMGB1 therapy for intracerebral hemorrhage (2017)
  • Author(s): 王登莉、劉克約、和氣秀徳、勅使川原匡、森秀治、西堀正洋
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール
  • Year and Date: 2017-03-15
• [Presentation] Role of spinal high mobility group box-1 associated receptors in the induction of central post-stroke pain and the involvement of glia cells in this mechanism (2017)
  • Author(s): 松浦渉、原田慎一、劉克約、西堀正洋、徳山尚吾
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎ブリックホール
  • Year and Date: 2017-03-15
• [Presentation] 脳卒中後疼痛における脊髄のhigh mobility group box-1/nitiric oxide synthetaseシグナルの関与 (2017)
  • Author(s): 松浦渉、原田慎一、劉克約、西堀正洋、徳山尚吾
  • Organizer: 第131回日本薬理学会近畿部会
• [Presentation] 抗HMGB1抗体はマウスのピロカルピン誘発痙攣におけるBBB破綻と脳内炎症からマウスを保護する (2017)
  • Author(s): 西堀正洋、富麗、劉克約、和氣秀徳、高橋英夫、森秀治
  • Organizer: 第40回日本神経科学大会
• [Presentation] 神経障害性疼痛モデルマウスにおけるうつ様行動とHMGB1発現解析 (2017)
  • Author(s): 富村昌暉、中島一恵、吉井稔紀、張 芳芳、劉 克約、西堀正洋、仲田義啓、森岡徳光
  • Organizer: 第132回日本薬理学会近畿部会
• [Presentation] 脊髄後角におけるHMGB1 による疼痛惹起メカニズムに対するIL-1βの関与 (2017)
  • Author(s): 宮内一希、張 芳芳、中島一恵、劉 克約、西堀正洋、仲田義啓、森岡徳光
  • Organizer: 第132回日本薬理学会近畿部会
• [Presentation] 脳卒中後疼痛に対する脊髄HMGB1関連受容体シグナルおよびグリア細胞の関与 (2017)
  • Author(s): 松浦歩、原田慎一、劉克約、西堀正洋、徳山尚吾
  • Organizer: 第132回日本薬理学会近畿部会
• [Presentation] メトホルミンはHMGB1 に直接結合しその炎症促進作用を抑制する (2017)
  • Author(s): 坂田菜摘、堀内崇弘、鳴海善洋、木村朋寛、林隆史、長野圭介、劉克約、西堀正洋、突田壮平、山田哲也、片桐秀樹、白川龍太郎、堀内久徳
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] 脊椎HMGB1関連受容体/グリア細胞/NOSシグナルを介する脳卒中後疼痛の発現機序の解明 (2017)
  • Author(s): 松浦渉、原田慎一、劉克約、西堀正洋、徳山尚吾
  • Organizer: 第138回日本薬理学会関東部会
• [Presentation] ラット脳内出血モデルにおける2次性炎症反応と抗HMGB1抗体効果 (2016)
  • Author(s): 西堀正洋、王登莉、劉克約、和氣秀徳、勅使川原匡、森秀治
  • Organizer: 第37回日本炎症・再生医学会，京都，2016
  • Place of Presentation: 京都市勧業館みやこめっせ
• [Presentation] Anti-HMGB1 mAb attenuates cerebral vasospasm and brain injury after subarachnoid hemorrhage in rats (2016)
  • Author(s): 勅使川原匡、春間純、菱川朋人、王登莉、劉克約、和氣秀徳、森秀治、高橋英夫、杉生憲志、伊達勲、西堀正洋
  • Organizer: 第130会日本薬理学会近畿部会
  • Place of Presentation: 京都大学百周年時計台記念館
• [Remarks] 脳虚血におけるHMGB1の動態と虚血性脳障害に対する抗HMGB1抗体の効果
  • URL: http://www.okayama-u.ac.jp/user/pharmaco/research.html