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2001 Fiscal Year Final Research Report Summary

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)
Project Period (FY) 1999 – 2001
KeywordsErythropoietin / Cerebral ischemia / Cell death / Bcl-x_L / bcl-2
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.

  • Research Products

    (24 results)

All Other

All Publications (24 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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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
  • [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

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Published: 2003-09-17  

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