Angiogenesis therapy against cerebral ischemic disease

• Project/Area Number: 17591521
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: Oita University
• Principal Investigator: KOBAYASHI Hidenori Oita University, Faculty of Medicine, Professor (80126581)
• Co-Investigator(Kenkyū-buntansha): HIKAWA Takamitsu Oita University, Faculty of Medidne, Lecturer (20238257) ; MORISHIGE Masaki Oita University, Facility of Medicine, Research Associate (60381050)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,570,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥270,000); Fiscal Year 2007: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2006: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
• Keywords: HIF-1 α / Cerebral Infarction / VEGF / Ischemic Tolerance / GGA / HSP-70 / Angiogenesis / Hypoxia / HIF-1 / HSP70

Research Abstract

Hyoxia-inducible factor 1(HIF-1) is a transcription factor that regulates the adaptive response to hypoxia in mammalian cells. It consists of a regulatory subunit HIF-1α, which accumulates under hypmic conditions, and constitutively expressed subunit, HIF-1β. We investigated HIF-1α naked DNA-induced angiogenesis in a cerebral ischemic model in vivo. We utilized a rat encephalo-myo-synangiosis model and inoculated HIF-1α naked DNA on the brain surface or temporal muscle. We analyzed HIF-1α induced angiogenic factors and collateral circulation. A histological section treated with HIF-1α DNA showed an increased expression of HIF-1α and VEGF with collateral circulation, in comparison with control DNA HIF-1α transcription factor is able to promote significant angiogenesis development.
Geranylgeranylacetone (GGA) is known as an antinuclear agent and more recently as a heat shock protein (HSP) inducer. This study evaluated the neuroprotective effect of GGA against cerebral infarction induced by permanent left middle cerebral artery (MCA) occlusion in rats. GGA was given orally in various regimens prior to MCA ocdusion Pretreatment with a single oral GGAdose (800 mg/kg) 48 hours before ischemia significantly attenuated cerebral infarction volume. A significant increase in HSP70 immunoreactivity was found in the neocortex in GGA-treated animals with or without ischemia. Pretreatment with a single oral dose of GGA provides an important tool for exploring the mechanisms of neuroprotection against cerebral ischemic neuronal damage.

Research Products

• [Journal Article] GEP 100 links epidermal growth factor receptor signaling to Arf6 activation to induce breast cancer invasion (2008)
  • Author(s): Morishige M
  • Journal Title: Nature Cell Biol 10 Pages: 85-92
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] GEP 100 links epidermal growth factor receptor signaling to Arf6 activation to induce breast cancer invasion (2008)
  • Author(s): Morishige, M., Hashimoto, S., Ogawa, E., Toda, Y., Kotani, H., Hirose, M., Wei, S., Hashimoto, A., Yamada, A., Yano, H., Mazaki, Y., Kodama, H., Nio, Y., Manabe, T., Wada, H., Kobayashi, H., Sabe, H.
  • Journal Title: Nature Cell Biol 10 Pages: 85-92
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] GEP 100 links epidermal growth factor receptor signaling to Arf6 activation to induce breast cancer invasion. (2008)
  • Author(s): Morishige M
  • Journal Title: Nature Cell Biology 10 Pages: 85-92
  • Peer Reviewed
• [Journal Article] 血管新生研究と脳神経外科治療への展開 (2006)
  • Author(s): 阿部 竜也
  • Journal Title: 脳神経外科 34 Pages: 123-132
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Intraoperative corticomuscular motor evoked potentials for evaluation of motor function:a comparison with corticospinal D and I waves (2006)
  • Author(s): Fujiki M
  • Journal Title: J Neurosurg 104 Pages: 85-92
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Reduced short latency afferent inhibition in diffuse axonal injury patients with memory impairment (2006)
  • Author(s): Fujiki M
  • Journal Title: Neurosci Lett 405 Pages: 226-230
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Role of protein kinase C in neuropotective effect of geranylgeranylacetone,a noninvasive inducing agent of heat shock protein,on delayed neuronal death caused by transient ischemia in rats (2006)
  • Author(s): Fujiki M
  • Journal Title: J Neurotrauma 23 Pages: 1164-1178
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Geranylgeranylacetone,a noninvasive heat shock protein inducer,induces protein kinase C and leads to neuroprotection against cerebral infarction in rats (2006)
  • Author(s): Uchida S
  • Journal Title: Neurosci Lett 396 Pages: 220-224
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Induced angiogenesis under cerebral ischemia by cyclooxygenase 2 and hypoxia-inducible factor naked DNA in a rat indirect-bypass model (2006)
  • Author(s): Anan M
  • Journal Title: Neurosci Lett Pages: 118-123
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] 血管新生研究と脳神経外科治療への展開 (2006)
  • Author(s): 阿部, 竜也, 上田, 徹, 藤木, 稔, 古林, 秀則
  • Journal Title: 脳神経外科 34(2) Pages: 123-132
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Intraoperative corticomuscular motor evoked potentials for evaluation of motor function : a comparison with cortico-spinal D and I waves- (2006)
  • Author(s): Fujiki, M., Furukawa, Y., Kamida, T., Anan, M., Inoue, R., Abe, T., Kobayashi, H.
  • Journal Title: J Neurosurg 104 Pages: 85-92
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Reduced short latency afferent inhibition in diffuse axonal injury patients with memory impairment (2006)
  • Author(s): Fujiki, M., Hikawa, T., Abe, T., Ishii, K., Kobayashi, H.
  • Journal Title: Neurosci Lett 405 Pages: 226-230
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Role of protein kinase C in neuropotective effect of geranylgeranylacetone, a noninvasive inducing agent of heal shock protein, on delayed neuronal death caused by transient ischemia in rats (2006)
  • Author(s): Fujiki, M., Hikawa, T., Abe, T., Uchida, S., Morishige, M., Sugita, K., Kobayashi, H.
  • Journal Title: J Neurotrauma 23(7) Pages: 1164-1178
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Geranylgeranylacetone, a noninvasive heat shock protein inducer, induces protein kinase C and leads to neuroprotection against cerebral infarction in rats (2006)
  • Author(s): Uchida, S., Fujiki, M., Nagai, Y., Abe, T., Kobayashi, H.
  • Journal Title: Neurosci Lett 396(3) Pages: 220-224
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Induced angiogenesis under cerebral ischemia by cyclo-oxygenase 2 and hypoxia-inducible factor naked DNA in a To indirect-bypass model (2006)
  • Author(s): Anan, M., Abe, T., Matsuda, T., Ishii, K., Kamida, T., Fujiki, M., Kobayashi, H.
  • Journal Title: Neurosci Lett 409(2) Pages: 118-123
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 血管新生研究と脳神経外科治療への展望 (2006)
  • Author(s): 阿部竜也
  • Journal Title: 脳神経外科 34・2 Pages: 123-132
• [Journal Article] Intraoperative corticomuscular motor evoked potentials for evaluation of motor function : a comparison with corticospinal D and I waves. (2006)
  • Author(s): Fujiki M
  • Journal Title: J Neurosurg 104 Pages: 85-92
• [Journal Article] Reduced short latency afferent inhibition in diffuse axonal injury patients with memory impairment. (2006)
  • Author(s): Fujiki M
  • Journal Title: Neurosci Lett 405 Pages: 226-230
• [Journal Article] Targeting AMAP1 and cortactin binding bearing an atypical srchomology3/praline interface for prevention of breast cancer invasion and metastasis. (2006)
  • Author(s): Hashimoto S
  • Journal Title: Proc Natl Acad Sci USA 103・18 Pages: 7036-7041
• [Journal Article] Role of protein kinase C in neuroprotective effect of geranylgeranylacetone, a noninvasive inducing agent of heat shock protein, on delyayed neuronal death by transient ischemia in rats. (2006)
  • Author(s): Fujiki M
  • Journal Title: J Neurotrauma 23・7 Pages: 1164-1178
• [Journal Article] Induced angiogenesis under cerebral ischemia by cyclooxygenase 2 and hypoxia inducible factor naked DNA in a rat indirect-bypass model. (2006)
  • Author(s): Anan M
  • Journal Title: Neurosci Lett 409 Pages: 118-123
• [Journal Article] Geranylberanylacetone, a noninvasive heat shock protein inducer induces protein kinase C and leads to neuroprotection against cerebral infarction in rats. (2006)
  • Author(s): Uchida S
  • Journal Title: Neurosci Lett 396・3 Pages: 220-224
• [Journal Article] 血管新生研究と脳神経外科治療への展開 (2006)
  • Author(s): 阿部 竜也
  • Journal Title: 脳神経外科 34・2 Pages: 123-132
• [Journal Article] Neuroprotective effect of geranylgeranylacetone:a noninvasive heat shock protein inducer on cerebral infarction in rats (2005)
  • Author(s): Nagai Y
  • Journal Title: Neurosci Lett 374 Pages: 183-188
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Mutant IκB_α suppresses hypoxia-induced VEGF expression through down-regulation of HIF-1α and COX-2 in human glioma cells (2005)
  • Author(s): Kimba Y
  • Journal Title: Oncol Res 15 Pages: 139-149
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Hypoxia-lnducible factor-1α DNA Induced angiogenesis in a rat cerebral Ischemic model (2005)
  • Author(s): Matsuda T
  • Journal Title: Neurol Res 27 Pages: 503-508
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Geranylgeranylacetone limits secondary injury, neuronal death,and progressive necrosis and cavitation after spinal cord injury (2005)
  • Author(s): Fujiki M
  • Journal Title: Brain Res 1053 Pages: 175-184
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Neuroprotective effect of Donepezil,a nicotinic acetylcholine-receptor activator,on cerebral infarction in rats (2005)
  • Author(s): Fujiki M
  • Journal Title: Brain Res 1043 Pages: 236-241
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Neuroprotective effect of geranylgeranylacetone : a noninvasive heat shock protein inducer on cerebral infarction in rats (2005)
  • Author(s): Nagai, Y., Fujiki, M., Inoue, R., Uchida, S., Abe, T., Kobayashi, H., Cetinalp, NE.
  • Journal Title: Neurosci Lett 374(3) Pages: 183-188
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mutant I κBα, suppresses hypoxia-induced VEGF expression Through down-regulation of HIF-1 α and COX-2 in human glioma cells (2005)
  • Author(s): Kimba, Y., Abe, T., Wu, JL., Inoue, R., Fujiki, M., Kohno, K., Kobayashi, H.
  • Journal Title: Oncol Res 15 Pages: 139-149
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hypoxia-Inducible factor-1α DNA Induced angiogenesis in a rat cerebral Ischemic model (2005)
  • Author(s): Matsuda, T., Abe, T., Wu, JL., Fujiki, M., Kobayashi, H.
  • Journal Title: Neurol Res 27(7) Pages: 503-508
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Geranylgeranylacetone limits secondary injury, neuronal death, and progressive necrosis and cavitation after spinal cord injury (2005)
  • Author(s): Fujiki, M., Furukawa, Y., Kobayashi, H., Abe, T., Ishii, K.
  • Journal Title: Brain Res 1053(1-2) Pages: 175-184
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Neuroprotective effect of Donepezil, a nicotinic acetylcholine-receptor activator, on cerebral infarction i rats (2005)
  • Author(s): Fujiki, M., Kobayashi, H., Uchida, S., Inoue, R., Ishii, K.
  • Journal Title: Brain Res 1043(1-2) Pages: 236-241
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Neuroprotective effect of geranylgeranylacetone : a noninvasive heat shock protein inducer on cerebral infarction in rats. (2005)
  • Author(s): Nagai, Yasuyuki
  • Journal Title: Neurosci Lett 374・3 Pages: 183-188
• [Journal Article] Mutant I κ B_α suppresses hypoxia-induced VEGF expression through down-regulation of HIF-1 α and COX-2 in human glioma cells. (2005)
  • Author(s): Kimba, Yoshihira
  • Journal Title: Oncol Res 15 Pages: 139-149
• [Journal Article] Hypoxia-Inducible factor-1 α DNA Induced angiogenesis in a rat cerebral Ischemic model. (2005)
  • Author(s): Matsuda, Takeshi
  • Journal Title: Neurol Res 27・7 Pages: 503-508
• [Journal Article] Geranylgeranylacetone limits secondary injury, neuronal death, and progressive necrosis and cavitation after spinal cord injury. (2005)
  • Author(s): Fujiki, Minoru
  • Journal Title: Brain Res 1053・1-2 Pages: 175-184
• [Book] 脳腫瘍手術の進歩と限界 (2006)
  • Author(s): 古林秀則
  • Publisher: 医歯薬出版
• [Book] 磁気刺激法の基礎と応用(分担) (2005)
  • Author(s): 藤木 稔
  • Publisher: 医歯薬出版