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，是红细胞生成的主要调节剂，在过去十年中已在临床医学中用于治疗肾性贫血。最近，一系列证据表明 EPO 及其受体在大脑中的表达表明 EPO-EPO 受体 (EPOR) 系统也在大脑中发挥作用。在本研究中，我们研究了促红细胞生成素 (EPO) 的作用体内和体外缺血诱导的神经元损伤的研究。体内实验表明，EPO 可以挽救沙鼠 3 分钟短暂前脑缺血后海马 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) 闭塞后的梗塞体积。 EPO 还改善了沙鼠缺血引起的学习障碍和 SHR 缺血引起的位置导航障碍。此外，脑室内注射可溶性EPOR可抑制EPO信号传递，从而增强缺血性神经元损伤。Western blot和RT-PCR分析表明，EPO注射可诱导缺血沙鼠海马CA 1区Bcl-x_L mRNA和蛋白的表达明显增强。比车辆输注。原位杂交组织化学也表明大鼠MCA闭塞后脑皮质梗死病灶外周EPOR mRNA表达上调。这表明神经元中EPOR数量的增加促进了EPO信号的传递，有利于神经元的存活。体外实验表明，EPO可以减轻化学缺氧引起的神经元损伤，并上调培养神经元中的Bcl-x_L mRNA和蛋白表达。 EPO 可能通过抗凋亡基因产物 Bcl-x_L 的上调来保护神经元免受缺氧和缺血性损伤。本研究提出了 EPO 对患者的可能治疗应用伴有中风。

项目成果

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