Study for regeneration of function in neonatal hypoxic-ischemic encephalopathy using animal model of slowly progressive brain damage in rats

• Project/Area Number: 20590552
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Fukuoka University
• Principal Investigator: MISHIMA Kenichi Fukuoka University, 薬学部, 准教授 (00320309)
• Co-Investigator(Kenkyū-buntansha): FUJIWARA Michihiro 福岡大学, 薬学部, 教授 (10091331) ; IWASAKI Katsunori 福岡大学, 薬学部, 教授 (10183196)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2009: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2008: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 新生児 / 低酸素性虚血性脳症 / 緩徐進行性脳損傷 / 機能再生 / 性差 / 脳虚血 / 学習・記憶 / 再生 / 卵膜由来間葉系幹細胞 / 細胞治療

Research Abstract

We recently reported that rehabilitative training tasks during adolescence improve spatial learning impairment following neonatal hypoxic-ischemic (HI) injury in rats without histological improvement. In the present study we focused on sex differences. Wister rat pups were exposed to a unilateral hypoxic-ischemic insult at 7 days of age. Six weeks after hypoxia-ischemia, rehabilitative training tasks were started. The tasks consisted of the plus maze, the eight-arm radial maze, and the choice reaction time task. Sixteen weeks after the HI insult, the water maze task was performed to evaluate spatial learning ability. Afterwards, we morphologically examined brain injury. Our rehabilitative training significantly improved swimming time and length in females but not in males. Likewise, the training ameliorated infarct areas in the injured cerebral hemisphere in females but not in males. These results suggest that it may be important to develop and evaluate cognitive rehabilitation programs for children with brain injury on the basis of gender.

Research Products

• [Journal Article] Sex differences in the benefits of rehabilitative training during adolescence following neonatal hypoxia-ischemia in rats (2010)
  • Author(s): Tsuji M, Aoo N, Harada K, Sakamoto Y, Akitake Y, Irie K, Mishima K, Ikeda T, Fujiwara M
  • Journal Title: Exp Neurol. 226(2) Pages: 285-292
  • Peer Reviewed
• [Journal Article] Allogeneic administration of fetal membrane-derived mesenchymal stem cells attenuates acute myocarditis in rats (2010)
  • Author(s): Ishikane S, Yamahara K, Sada M, Harada K, Kodama M, Ishibashi-Ueda H, Hayakawa K, Mishima K, Iwasaki K, Fujiwara M, Kangawa K, Ikeda T
  • Journal Title: J Mol Cell Cardiol. 49(5) Pages: 753-761
  • Peer Reviewed
• [Journal Article] Ameliorating effects of Kangen-karyu on neuronal damage in rats subjected to repeated cerebral ischemia (2010)
  • Author(s): Pu F, Kaneko T, Enoki M, Irie K, Okamoto T, Sei Y, Egashira N, Oishi R, Mishima K, Kamimura H, Iwasaki K, Fujiwara M
  • Journal Title: J Nat Med. 64(2) Pages: 167-174
  • NAID: 10027709454
  • Peer Reviewed
• [Journal Article] ADAMTS13 gene deletion aggravates ischemic brain damage: a possible neuroprotective role of ADAMTS13 by ameliorating post-ischemic hypoperfusion (2010)
  • Author(s): Fujioka M, Hayakawa K, Mishima K, Kunizawa A, Irie K, Higuchi S, Nakano T, Muroi C, Fukushima H, Sugimoto M, Banno F, Kokame K, Miyata T, Fujiwara M, Okuchi K, Nishio K
  • Journal Title: Blood 115(8) Pages: 1650-1653
  • Peer Reviewed
• [Journal Article] Inhibition of reactive astrocytes with fluorocitrate retards neurovascular remodeling and recovery after focal cerebral ischemia in mice (2010)
  • Author(s): Hayakawa K, Nakano T, Irie K, Higuchi S, Fujioka M, Orito K, Iwasaki K, Jin G, Lo EH, Mishima K, Fujiwara M
  • Journal Title: J Cereb Blood Flow Metab. 30(4) Pages: 871-82
  • Peer Reviewed
• [Journal Article] Sex differences in the benefits of rehabilitative training during adolescence following neonatal hypoxia-ischemia in rats. (2010)
  • Author(s): Tsuji M., et al.
  • Journal Title: Exp Neurol. Volume: 226(2) Pages: 285-292
  • Peer Reviewed
• [Journal Article] Allogeneic administration of fetal membrane-derived mesenchymal stem cells attenuates acute myocarditis in rats. (2010)
  • Author(s): Ishikane S., et al.
  • Journal Title: J Mol Cell Cardiol. Volume: 49(5) Pages: 753-761
  • Peer Reviewed
• [Journal Article] Neuroprotective Effect of Repeated Treatment with Hericium Erinaceum in Mice Subjected to Middle Cerebral Artery Occlusion. (2010)
  • Author(s): Hazekawa M., et al.
  • Journal Title: J Health Science Volume: 56(3) Pages: 296-303
  • Peer Reviewed
• [Journal Article] ADAMTS13 gene deletion aggravates ischemic brain damage : a possible neuroprotective role of ADAMTS 13 by ameliorating postischemic hypoperfusion (2010)
  • Author(s): Fujioka M., et al.
  • Journal Title: Blood 115(8) Pages: 1650-3
  • Peer Reviewed
• [Journal Article] Ameliorating effects of Kangen-karyu on neuronal damage in rats subjected to repeated cerebral ischemia (2010)
  • Author(s): Pu F., et al.
  • Journal Title: J Nat Med. 64 Pages: 167-174
  • Peer Reviewed
• [Journal Article] Therapeutic time window of cannabidiol treatment on delayed ischemic damage via high-mobility group box1-inhibiting mechanism (2009)
  • Author(s): Hayakawa K, Irie K, Sano K, Watanabe T, Higuchi S, Enoki M, Nakano T, Harada K, Ishikane S, Ikeda T, Fujioka M, Orito K, Iwasaki K, Mishima K, Fujiwara M
  • Journal Title: Biol Pharm Bull. 32(9) Pages: 1538-44
  • NAID: 130000117280
  • Peer Reviewed
• [Journal Article] Neuroprotective effects of Kangen-karyu on spatial memory impairment in an 8-arm radial maze and neuronal death in the hippocampal CA1 region induced by repeated cerebral ischemia in rats (2009)
  • Author(s): Pu F, Motohashi K, Kaneko T, Tanaka Y, Manome N, Irie K, Takata J, Egashira N, Oishi R, Okamoto T, Sei Y, Yokozawa T, Mishima K, Iwasaki K, Fujiwara M
  • Journal Title: J Pharmacol Sci. 109(3) Pages: 424-340
  • NAID: 10025735292
  • Peer Reviewed
• [Journal Article] Therapeutic time window of cannabidiol treatment on delayed ischemic damage via high-mobility group boxl-inhibiting mechanism (2009)
  • Author(s): Hayakawa K., et al.
  • Journal Title: Biol Pharm Bull 32(9) Pages: 1538-44
  • Peer Reviewed
• [Journal Article] Neuroprotective effects of Kangen-karyu on spatial memory impairment in an 8-arm radial maze and neuronal death in the hippocampal CA1 region induced by repeated cerebral ischemia in rats. (2009)
  • Author(s): Pu F., et al.
  • Journal Title: J Pharmacol Sci. 109(3) Pages: 424-430
  • Peer Reviewed
• [Journal Article] Allogeneic injection of fetal membrane-derived mesenchymal stem cells induces therapeutic angiogenesis in a rat model of hind limb ischemia (2008)
  • Author(s): Ishikane S, Ohnishi S, Yamahara K, Sada M, Harada K, Mishima K, Iwasaki K, Fujiwara M, Kitamura S, Nagaya N, Ikeda T
  • Journal Title: Stem Cells. 26(10) Pages: 2625-2633
  • Peer Reviewed
• [Journal Article] Cannabidiol prevents a post-ischemic injury progressively induced by cerebral ischemia via a high-mobility group box1-inhibiting mechanism (2008)
  • Author(s): Hayakawa K, Mishima K, Irie K, Hazekawa M, Mishima S, Fujioka M, Orito K, Egashira N, Katsurabayashi S, Takasaki K, Iwasaki K, Fujiwara M
  • Journal Title: Neuropharmacology 55(8) Pages: 1280-6
  • Peer Reviewed
• [Journal Article] Delayed treatment with minocycline improves neurological impairment via activated microglia expressing high-mobility group box1 inhibiting mechanism (2008)
  • Author(s): Hayakawa K, Mishima K, Nozako M, Irie K, Hazekawa M, Mishima S, Fujioka M, Orito K, Egashira N, Iwasaki K, Fujiwara M
  • Journal Title: Stroke 39(3) Pages: 951-958
  • Peer Reviewed
• [Journal Article] Allogeneic injection of fetal membrane-derived mesenchymal stem cells induces therapeutic angiogenesis in a rat model of hind limb ischemia (2008)
  • Author(s): Ishikane S., et al.
  • Journal Title: Stem Cells 26(10) Pages: 2625-2633
  • Peer Reviewed
• [Journal Article] Cannabidiol prevents a post-ischemic injury progressively induced by cerebral ischemia via a high-mobility group boxl-inhibitin mechanism (2008)
  • Author(s): Hayakawa K., et al.
  • Journal Title: Neuropharmacology 55(8) Pages: 1280-1286
  • Peer Reviewed
• [Presentation] 新生児低酸素性虚血性脳症モデルラットにおける虚血同側への異常な回転行動に対するドーパミン神経系の関与 (2010)
  • Author(s): 坂元佑哉、三島健一、秋武義治、入江圭一、宮崎蓉子、栫千恵、窪田香織、桂林秀太郎、高崎浩太郎、岩崎克典、藤原道弘
  • Organizer: 第63回日本薬理学会西南部会
  • Place of Presentation: 鹿児島
  • Year and Date: 2010-11-26
• [Presentation] 新生児低酸素性虚血性脳症モデルラットにおける虚血同側への異常な回転行動に対するドーパミン神経系の関与 (2010)
  • Author(s): 坂元佑哉, et al.
  • Organizer: 第63回日本薬理学会西南部会
  • Place of Presentation: 鹿児島, かごしま県民交流センター
  • Year and Date: 2010-11-26
• [Presentation] 新生児低酸素性虚血性脳症(HIE)モデルラットの緩徐進行性脳損傷に対するアストロサイトに発現したカンナビノイド受容体の関与 (2010)
  • Author(s): 宮崎蓉子、坂元佑哉、石兼真、原田和彦、入江圭一、池田智明、松山清、三島健司、桂林秀太郎、高崎浩太郎、三島健一、岩崎克典、藤原道弘
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-28
• [Presentation] 低酸素性虚血により生じる緩徐進行性脳損傷の性差の発現には活性化アストロサイトが関与している (2010)
  • Author(s): 坂元佑哉、石兼真、原田和彦、三島健一、入江圭一、樋口聖、白川敦規、宮崎蓉子、池田智明、桂林秀太郎、高崎浩太郎、岩崎克典、藤原道弘
  • Organizer: 第83回日本薬理学会年会
  • Place of Presentation: 大阪
  • Year and Date: 2010-03-18
• [Presentation] 新生児低酸素性虚血性脳症(HIE)モデルラットの緩徐進行性脳損傷に対するアストロサイトに発現したカンナビノイド受容体の関与 (2010)
  • Author(s): 宮崎蓉子, et al.
  • Organizer: 第130年会日本薬学会
  • Place of Presentation: 岡山, 岡山コンベンションセンター
• [Presentation] 下肢虚血モデルラットを用いた卵膜由来間葉系幹細胞の他家細胞移植による血管新生効果の検討 (2009)
  • Author(s): 石兼真、池田智明、原田和彦、三島健一、岩崎克典、藤原道弘
  • Organizer: 第26回日本薬学会九州支部大会
  • Place of Presentation: 福岡
  • Year and Date: 2009-12-12
• [Presentation] Ovarievctomy gets worse the brain damage and learning impairment by hypoxic-ischemia in neonatal rats (2009)
  • Author(s): Y.Sakamoto, S.Ishikane, K.Harada, K.Mishima, K.Irie, T.Nakashima, S.Higuchi, A.Shirakawa, Y.Miyazaki, T.Ikeda, S.Katsurabayashi, T.Takasaki, K.Iwasaki, M.Fujiwara
  • Organizer: Neuroscience
  • Place of Presentation: Chicago,USA
  • Year and Date: 2009-10-15
• [Presentation] Therapeutic Angiogenesis by Transplantation of Allogeneic Fetal Membrane-Derived Mesenchymal Stem Cells (2009)
  • Author(s): Ishikane S, Nagaya N, Yamahara K, Sada M, Harada K, Mishima K, Iwasaki K, Fujiwara M, Ikeda T
  • Organizer: American College of Cardiology 58th Annual Scientific Session
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2009-03-28
• [Presentation] 下肢虚血モデルに対するヒト卵膜由来間葉系幹細胞移植による血管新生効果 (2009)
  • Author(s): 原田和彦、大西俊介、山原研一、佐田正晴、石兼真、大谷健太郎、中村篤宏、三島健一、岩崎克典、藤原道弘、寒川賢治、北村惣一郎、永谷憲歳、池田智明
  • Organizer: 第8回日本再生医療学会総会
  • Place of Presentation: 東京
  • Year and Date: 2009-03-05
• [Presentation] Estradiol suppresses slowly progressive brain damage with learning impairment induced by hypoxia-ischemic in neonatal rats (2009)
  • Author(s): Sakamoto Y., et al.
  • Organizer: Neuroscience 2009, Annual Meeting
  • Place of Presentation: Chicago, USA
• [Presentation] A new behavioral method for evaluating irritable behavior using ultrasonic vocalizations in rats. (2009)
  • Author(s): Yamada Y., et al.
  • Organizer: The 82^<nd> Annual Meeting of the Japanese Pharmacological Society
  • Place of Presentation: Yokohama
• [Presentation] Therapeutic potential of mesenchymal stem cells derived from three different layers of human fetal membrane in hindlimb ischemia model (2008)
  • Author(s): Harada K, Ohnishi S, Yamahara K, Sada M, Ishikane S, Mishima K, Iwasaki K, Fujiwara M, Kangawa K, Kitamura S, Nagaya N, Ikeda T
  • Organizer: American Heart Association Scientific Session
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2008-11-10
• [Presentation] Implantation of encapsulated glial cell line-derived neurotrophic factor-secreting cells prevents long-lasting learning impairment following neonatal hypoxic-ischemic brain insult in rats (2008)
  • Author(s): Katsuragi S, Ikeda T, Date I, Shingo T, Yasuhara T, Mishima K, Aoo N, Harada K, Egashira N, Iwasaki K, Fujiwara M, Ikenoue T
  • Organizer: 6th Hershey Conference
  • Place of Presentation: Harrisburg, USA
  • Year and Date: 2008-06-07
• [Presentation] Abnormal turning behavior but not ultrasonic vocalization correlates with hypoxic-ischemic brain injury in neonatal rats (2008)
  • Author(s): Harada K, Mishima K, Iwasaki K, Fujiwara M, Nagaya N, Iwasaki K, Fujiwara M
  • Organizer: 6th Hershey Conference
  • Place of Presentation: Harrisburg, USA
  • Year and Date: 2008-06-07
• [Presentation] Therapeutic potential of mesenchymal stem cells derived from three different layers of human fetal membrane in hindlimb ischemia model. (2008)
  • Author(s): Harada K., et ai.
  • Organizer: American Heart Association Scientific Session 2008
  • Place of Presentation: New Orleans
• [Presentation] Implantation of encapsulated glial cell line-derived neurotrophic factor-secreting cells prevents long-lasting learning impairment following neonatal hypoxic-ischemic brain insult in rats. (2008)
  • Author(s): Katsuragi S., et al.
  • Organizer: 6th Hershey Conference
  • Place of Presentation: Harrisburg
• [Presentation] Abnormal turning behavior but not ultrasonic vocalization correlates with hypoxic-ischemic brain injury in neonatal rats (2008)
  • Author(s): Harada K., et al.
  • Organizer: 6th Hershey Conference
  • Place of Presentation: Harrisburg
• [Book] In Handbook of Green Tea and Health Research(Edited by Mckinley H. and Jamieson M. Neuroprotective effect of theanine on cerebral ischemia ISBN:978-1-60741-045-4) (2009)
  • Author(s): Egashira N, Mishima K, Iwasaki K, Oishi R, Fujiwara M
  • Publisher: Nova Science Publishers, Inc., N.Y.
• [Remarks] ホームページ等
• [Patent(Industrial Property Rights)] 生体試料中2-アラキドノイルグリセロールの定量法 (2010)
  • Inventor(s): 入江圭一、藤原道弘、三島健一、樋口聖、三島健司、早川和秀、佐野和憲、佐藤朝光、秋武義治、荒木舞子、大治万喜子
  • Industrial Property Rights Holder: 福岡大学
  • Industrial Property Number: 2010-234486
  • Filing Date: 2010-10-19
• [Patent(Industrial Property Rights)] 生体内試料中2-アラキドノイルグリセロールの定量法 (2010)
  • Inventor(s): 入江圭一, et al.
  • Industrial Property Rights Holder: 福岡大学
  • Industrial Property Number: 2010-234486
  • Filing Date: 2010-10-19
• [Patent(Industrial Property Rights)] 母乳由来の脂質およびその誘導体を有効成分とする抗菌ペプチドの発現誘導剤あるいは産生促進剤 (2009)
  • Inventor(s): 佐藤朝光,藤原道弘,入江圭一,三島健一,見明史雄,鹿志毛信広,早野智大,添田秦司
  • Industrial Property Rights Holder: 福岡大学
  • Industrial Property Number: 2009-121853
  • Filing Date: 2009-05-20