| Project/Area Number | 11470291 |
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cerebral neurosurgery
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| Research Institution | Ehime University |
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Principal Investigator |
SAKANAKA Masahiro Ehime University, Faculty of Medicine, Professor, 医学部, 教授 (60170601)
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| 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)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed(Fiscal Year 2001)
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| 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)
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| Keywords | Erythropoietin / 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 |
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| 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.
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