Excitotoxic injury to developing oligodendrocytes

对发育中的少突胶质细胞的兴奋性毒性损伤

• 批准号: 6330940
• 负责人: Frances E Jensen
• 金额: $ 19.61万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-10 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6330940
• 关键词: AMPA receptors; age difference; calcium flux; cerebral ischemia /hypoxia; cytotoxicity; developmental neurobiology; free radicals; glutamate receptor; glutamates; laboratory rat; neuroprotectants; neurotoxicology; neurotransmitter antagonist; oligodendroglia; oxidative stress

Substantial evidence implicates hypoxic/ischemic white matter injury as a cause of periventricular leukomalacia (PVL). The excitatory neurotransmitter glutamate is released from axons and glia under hypoxic/ischemic conditions. We now show that glutamate can be toxic to developing oligodendrocytes (OLs) via interaction with their alpha- amino-3-hydroxy-5-methyl-4e-isox-azole propionate (AMPA) and kainate receptors. Preliminary in vivo and in vitro results show that vulnerability to AMPA/kainate may be developmentally specific, enhanced in immature stages of OL differentiation. Furthermore, we now show that the developmental window of vulnerability to hypoxic/ischemic white matter injury parallels that for toxicity of AMPA agonists. A role for AMPA/kainate receptor-mediated toxicity in hypoxic/ischemic injury in the immature brain is supported by the observation that systemic treatment with the AMPA/kainate antagonist 6- nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-dione (NBQX) following hypoxia/ischemia attenuates white matter injury in the immature rat. The present project aims to understand the basis for the developmental specificity of AMPA/kainate injury to OLs, and whether this may be an important component of injury in the immature brain in vivo. The overall hypothesis of Project 4 is that maturation-dependent vulnerability of OLs to AMPA/kainate receptor-mediated excitotoxicity is an important cause of OL death in immature cerebral white matter, and thereby a potentially important factor in the pathogenesis of PVL. Aim 1. To determine whether the maturation-dependent vulnerability of OLs to AMPA/kainate toxicity relates to developmental differences in expression of AMPA/kainate receptors in OLs in vitro and in vivo. We will establish the developmental profile of AMPA/kainate receptors in primarily OLs; Aim 2. To characterize the mechanism of AMPA/kainate receptor- mediated toxicity in developing OLs. We will identify maturational differences in OL vulnerability and determine whether Ca++ influx and free radicals are mediating the death of developing OLs in vitro; Aim 3. To determine whether white matter injury induced by intracerebral injection of AMPA/kainate agonists is maturation dependent in rodent model of PVL; and Aim 4. To determine the maturational vulnerability of OLS to cerebral hypoxia/ischemia in the rat and the role of AMPA/kainate receptors in this vulnerability and whether glutamate antagonists represents a potential means of prevention of hypoxic- ischemic OL injury in the immature brain. The long term goal of this project is to define age-specific therapeutic strategies for the treatment and prevention of PVL.

大量证据表明缺氧/缺血性白质损伤是脑室周围白质软化（PVL）的原因之一。在缺氧/缺血条件下，轴突和神经胶质细胞释放兴奋性神经递质谷氨酸。我们现在表明，谷氨酸可能通过与少突胶质细胞的α-氨基-3-羟基-5-甲基-4e-异恶唑丙酸酯（AMPA）和红藻氨酸受体相互作用而对发育中的少突胶质细胞（OL）产生毒性。初步的体内和体外结果表明，对 AMPA/红藻氨酸的脆弱性可能具有发育特异性，在 OL 分化的未成熟阶段增强。此外，我们现在表明，易受缺氧/缺血性白质损伤影响的发育窗口与 AMPA 激动剂毒性的发育窗口相似。 AMPA/红藻氨酸受体介导的毒性在未成熟大脑缺氧/缺血性损伤中的作用得到了以下观察的支持：用 AMPA/红藻氨酸拮抗剂 6-硝基-7-氨磺酰基苯并(f)喹喔啉-2,3-二酮进行全身治疗(NBQX) 缺氧/缺血后可减轻未成熟大鼠的白质损伤。本项目旨在了解 AMPA/红藻氨酸对 OL 损伤的发育特异性的基础，以及这是否可能是体内未成熟大脑损伤的重要组成部分。项目 4 的总体假设是，成熟依赖性的 OL 对 AMPA/红藻氨酸受体介导的兴奋性毒性的脆弱性是未成熟脑白质中 OL 死亡的重要原因，因此也是 PVL 发病机制中的潜在重要因素。 目的 1. 确定 OL 对 AMPA/红藻氨酸毒性的成熟依赖性脆弱性是否与体外和体内 OL 中 AMPA/红藻氨酸受体表达的发育差异有关。我们将建立主要在 OL 中的 AMPA/红藻氨酸受体的发育概况；目标 2. 表征 AMPA/红藻氨酸受体介导的 OL 发育毒性机制。我们将确定 OL 脆弱性的成熟差异，并确定 Ca++ 流入和自由基是否在体外介导发育中 OL 的死亡；目的 3. 确定脑内注射 AMPA/红藻氨酸激动剂引起的白质损伤是否在啮齿动物 PVL 模型中具有成熟依赖性；目的 4. 确定大鼠 OLS 对脑缺氧/缺血的成熟脆弱性以及 AMPA/红藻氨酸受体在这种脆弱性中的作用，以及谷氨酸拮抗剂是否代表了预防未成熟大脑中缺氧缺血性 OL 损伤的潜在方法。该项目的长期目标是确定治疗和预防 PVL 的年龄特异性治疗策略。