Protective effects of erythropoietin on ischemic brain

促红细胞生成素对缺血性脑组织的保护作用

• 批准号: 11470291
• 负责人: SAKANAKA Masahiro
• 金额: $ 9.41万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470291/
• 关键词: 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

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.

促红细胞生成素（EPO）是一种糖蛋白，其作为红细胞生成的主要调节剂，并且在过去十年中已用于临床医学中用于治疗肾性贫血。近年来，大量证据表明EPO及其受体在脑内表达，提示EPO-EPO受体（EPOR）系统在脑内也发挥作用，本研究在体内外研究了促红细胞生成素（EPO）对缺血性神经元损伤的影响。在体实验表明，EPO在沙土鼠短暂前脑缺血3分钟后拯救海马CA 1区的神经元，并减少自发性高血压大鼠（SHR）永久性大脑中动脉（MCA）闭塞后的梗死体积。EPO还能改善沙土鼠缺血诱导的学习障碍和SHR缺血诱导的定位导航障碍。Western blot和RT-PCR分析显示，EPO可诱导缺血沙土鼠海马CA 1区Bcl-xL mRNA和蛋白表达增强，而EPO可抑制EPO信号传导。原位杂交组织化学结果显示，大鼠大脑中动脉闭塞后，大脑皮层梗死灶周围EPOR mRNA表达上调。体外实验表明，EPO能减轻化学性缺氧引起的神经元损伤，并能上调培养神经元中Bcl-x_L mRNA和蛋白的表达。促红细胞生成素可能通过上调抗凋亡基因产物Bcl-x_1保护神经元免受缺氧和缺血损伤本研究提出了EPO对中风患者的可能治疗应用。

项目成果

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