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Protective effects of erythropoietin on ischemic brain

Research Project

Project/Area Number 11470291
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Cerebral neurosurgery
Research InstitutionEhime University

Principal Investigator

SAKANAKA Masahiro  Ehime University, Faculty of Medicine, Professor, 医学部, 教授 (60170601)

Co-Investigator(Kenkyū-buntansha) TANAKA Junya  Ehime University, Faculty of Medicine, Professor, 医学部, 教授 (70217040)
SATO Kohji  Hamamatsu University, Faculty of Medicine, Professor, 教授 (80235340)
MAEDA Nobuji  Ehime University, Faculty of Medicine, Professor, 医学部, 教授 (50036464)
WEN Tong-chun  Ehime University, School of Medicine, Instructor, 医学部, 助手 (70284411)
DESAKI Junzo  Ehime University, Faculty of Medicine, Assistant Professor, 医学部, 講師 (00036451)
榊 三郎  愛媛大学, 医学部, 教授 (30116933)
Project Period (FY) 1999 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2001: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2000: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1999: ¥8,400,000 (Direct Cost: ¥8,400,000)
KeywordsErythropoietin / Cerebral ischemia / Cell death / Bcl-x_L / bcl-2 / 一酸化窒素 / 虚血傷害 / 低酸素傷害 / RT-PCR / ウエスタンブロット / スナネズミ / 海馬CA1領域 / 遅発性神経細胞死 / 受動的回避学習実験 / 細胞死関連遺伝子群
Research Abstract

Erythropoietin (EPO) is a glycoprotein that acts as a main regulator of erythropoiesis and has been used in clinical medicine over the last decade for the treatment of renal anemia. Recently, several lines of evidence demonstrate the expressions of EPO and its receptor in the brain suggesting that the EPO-EPO receptor (EPOR) system functions in the brain as well.
In the present study, we have investigated the effects of erythropoietin (EPO) on ischemia-induced neuronal damage in vivo and in vitro. In vivo experiments showed that EPO rescued neurons in the hippocampal CA 1 field after 3-min transient forebrain ischemia in gerbils and reduced infarct volume after permanent middle cerebral artery (MCA) occlusion in spontaneously hypertensive rats (SHR). EPO also ameliorated ischemia-induced learning disability in gerbils and ischemia-induced place navigation disability in SHR. Furthermore, intracerebroventricular infusion of soluble EPOR that could inhibit EPO signal transmission enhanced ischemic neuronal damage.
Western blot and RT-PCR analysis showed that EPO infusion induced significantly more intense expressions of Bcl-x_L mRNA and protein in the hippocampal CA 1 field of ischemic gerbils than did vehicle infusion. In situ hybridization histochemistry also indicated that EPOR mRNA was upregulated in the periphery of cerebrocortical infarct lesion after MCA occlusion in rats. This suggests that an increased number of EPOR in neurons facilitates the EPO signal transmission in favor of neuronal survival.
In vitro experiments showed that EPO attenuated neuronal damage caused by chemical hypoxia and upregulated Bcl-x_L mRNA and protein expressions in cultured neurons.
In conclusion, EPO protects neurons against hypoxic and ischemic insults possibly through upregulation of the anti-apoptotic gene product Bcl-x_L.The present study proposes the possible therapeutic application of EPO to patients with stroke.

Report

(4 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (39 results)

All Other

All Publications (39 results)

  • [Publications] Igase K, et al.: "An 18-mer peptide fragment of prosaposin ameliorates place navigation disability, cortical infarction, and retrograde thalamic degeneration in rats with focal cerebral ischemia"J Cereb Blood Flow Metab. 19. 298-306 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Fujita H, et al.: "Differential expressions of glycine transporter 1 and three glutamate transporter mRNAs in the hippocampus of gerbils with transient forebrain ischemia"J Cereb Blood Flow Metab. 19. 604-615 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hashimoto H, et al.: "Changes in guanylate cyclase activity in arteriolar smooth muscle cells and hemodynamics after ischemia-reperfusion in rats"Acta Neuropathol.. 98. 603-613 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka J, et al.: "Astrocytes prevent neuronal death induced by reactive oxygen and nitrogen species"GLIA. 28. 85-89 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakatsuka H, et al.: "Cytochrome c release from mitochondria to the cytosol was suppressed in the ischemia-tolerance-induced hippocampal CA1 region after 5-min forebrain ischemia in gerbils"Neuroscience Letters. 278. 53-56 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yang L, et al.: "Improvement of the viability of cultured rat neurons by the non-essential amino acids L-serine and glycine that upregulates expression of the anti-apoptotic gene product Bcl-w"Neuroscience Letters. 295. 97-100 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Fujita H, et al.: "Expressions of neuropilin-1, neuropilin-2 and semaphorin 3A mRNA in the rat brain after middle cerebral artery occlusion"Brain Research. 914. 1-14 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Wen T-C, et al.: "Induction of phosphorylated-Stat3 following focal cerebral ischemia in mice"Neuroscience Letters. 303. 153-156 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hata R, et al.: "Up-regulation of calcineurin Aβ mRNA in the alzheimer's disease brain : assessment by cDNA microarray"Biochemical Biophysical Research Communications. 284. 310-316 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sugamoto T, et al.: "The expression of basic fibroblast growth factor and vascular endothelial growth factor in prostatic adenocarcinoma : correlation with neovascularization"Anticancer Research. 21. 77-88 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Morita F, et al.: "Protective effect of a prosaposin-derived, 18-mer peptide on slowly progressive neuronal degeneration after brief ischemia"Journal of Cerebral Blood Flow and Metabolism. 21. 1295-1302 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Wen T-C, et al.: "Erythropoietin protects neurons against chemical hypoxia and cerebral ischemic injury by up-regulating Bcl-x_L expression"Journal of Neuroscience Research. (In press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Igawe K., et al.: "An 18-mer peptide fragment of prosaposin ameliorates place navigation disability, cortical infarction, and retrograde thalamic degeneration in rats with focal cerebral ischemia"J. Cereb. Bllod flow Metab.. 19. 298-306 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Fujita H., et al.: "Differential expressions of glycine transporter 1 and three glutamate transporter mRNAs in the hippocampus of gerbils with transient forebrain ischemia"J. Cereb. Bllod flow Metab.. 19. 604-615 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hashimoto H., et al.: "Changes in guanylate cyclase activity in arteriolar smooth muscle cells and hemodynamics after ischemia-reperfusion in rats"Acta Neuropathol.. 98. 603-613 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka J., et al.: "Astrocytes prevent neuronal death induced by reactive oxygen and nitrogen species"GLIA. 28. 85-96 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakatsuka H., et al.: "Cytochrome c release from mitochondria to the cytosol was suppressed in the ischemia-tolerance-induced hippocampal CA1 region after 5-min forebrain ischemia in gerbils"Neuroscience Letters. 278. 53-56 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yang L., et al.: "Improvement of the viability of cultured rat neurons by the non-essential amino acids L-serine and glycine that upregulates expression of the anti-apoptotic gene product Bcl-w"Neuroscience Letters. 295. 97-100 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Fujita H., et al.: "Expressions of neuropilin-1, neuropilin-2 and semaphorin 3A mRNA in the rat brain after middle cerebral artery occlusion"Brain Research. 914(2001). 1-14 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Wen T.-C., et al.: "Induction of phosphorylated-Stat3 following focal cerebral ischemia in mice"Neurosci. Lett.. 303. 153-156 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hata R., et al.: "Up-regulation of calcineurin Aβ mRNA in the alzheimer's disease brain: assessment by cDNA microarray."Biochemical Biophysical Research Communications. 284. 310-316 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sugamoto T., et al.: "The expression of basic fibroblast growth factor and vascular endothelial growth factor in prostatic adenocarcinoma : correlation with neovascularization"Anticancer Research. 21. 77-88 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Morita F., et al.: "Protective effect of a prosaposin-derived, 18-mer peptide on slowly progressive neuronal degeneration after brief ischemia"Jouranal of Cerebral Blood Flow and Metabolism. 21. 1295-1302 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Wen T.-C., et al.: "Erythropoietin protects neurons against chemical hypoxia and cerebral ischemic injury by up-regulating Bcl-x_L expression"Journal of Neuroscience Research. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Wen T-C, et al.: "Erythropoietin protects neurons against chemical hypoxia and cerebral ischemic injury by up-regulating Bcl-x_L expression"Journal of Neuroscience Research. (In press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Morita F, et al.: "Protective effect of a prosaposin-derived, 18-mer peptide on slowly progressive neuronal degeneration after brief ischemia"Journal of Cerebral Blood Flow and Metabolism. 21. 1295-1302 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fujita H, et al.: "Expressions of neuropilin-1, neuropilin-2 and semaphorin 3A mRNA in the rat brain after middle cerebral artery occlusion"Brain Research. 914. 1-14 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Wen T-C, et al.: "Induction of phosphorylated-Stat3 following focal cerebral ischemia in mice"Neuroscience Letters. 303. 153-156 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hata R, et al.: "Up-regulation of calcineurin A β mRNA in the alzheimer's disease brain : assessment by cDNA microarray"Biochemical Biophysical Research Communications. 284. 310-316 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sugamoto T, et al.: "The expression of basic fibroblast growth factor and vascular endothelial growth factor in prostatic adenocarcinoma : correlation with neovascularization"Anticancer Research. 21. 77-88 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 阪中雅広 ら: "脳卒中の克服:神経細胞保護因子の実用可能性"生体の科学. 51(1). 11-17 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nakatsuka H et al.: "Cytochrome c release from mitochondria to the cytosol was suppressed in the ischemia-tolerance-induced hippocampal CA1 region after 5-min forebrain ischemia in gerbils."Neuroscience Letters,. 278. 53-56 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nakatsuka H et al.: "Histochemical cytochrome c oxidase activity and caspase-3 in gerbil hippocampal CA1 neurons after transient forebrain ischemia."Neuroscience Letters,. 285. 127-130 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yang L et al.: "Improvement of the viability of cultured rat neurons by the non-essential amino acids L-serine and glycine that upregulates expression of the anti-apoptotic gene product Bcl-w."Neuroscience Letters,. 295. 97-100 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Chen Y-S et al.: "Effect of basic fibroblast growth factor (bFGF)-neutralizing antibody and platelet factor 4 on facial nerve regeneration."Experimental Neurology.. 155. 274-283 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Igase K et al.: "An 18-mer peptide fragment of prosaposin ameliorates place navigation disability,cortical infarction,and retrograde thalamic de"J Cereb.Blood Flow Metab.. 19. 298-306 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Fujita H et al.: "Differential expressions of glycine transporter 1 and three glutamate transporter mRNAs in the hippocampus of gerbils with tran"J Cereb.Blood Flow Metab.. 19. 604-615 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Watanabe H et al.: "Increase in p53 protein expression following cortical infarction in the spontaneously hypertensive rat."Brain Res.. 837. 38-45 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nakatsuka H et al.: "Release of cytochrome c from mitochondria to cytosol in gerbil hippocampal CA1 neurons after transient forebrain ischemia."Brain Res.. 849. 216-219 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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