Excitotoxic injury to developing oligodendrocytes

大量证据表明缺氧/缺血性白色物质损伤是脑室周围白质软化症（PVL）的一个原因。兴奋性神经递质谷氨酸在缺氧/缺血条件下从轴突和神经胶质释放。我们现在表明，谷氨酸可以通过与其α-氨基-3-羟基-5-甲基-4e-异恶唑丙酸酯（AMPA）和红藻氨酸受体的相互作用对发育中的少突胶质细胞（OL）有毒。初步的体内和体外结果表明，AMPA/红藻氨酸的脆弱性可能是发育特异性的，在OL分化的不成熟阶段增强。此外，我们现在表明，缺氧/缺血性白色物质损伤的脆弱性的发育窗口平行的AMPA激动剂的毒性。缺氧/缺血后用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（NBQX）全身治疗可减轻未成熟大鼠的白色损伤，这一观察结果支持了AMPA/红藻氨酸受体介导的毒性在未成熟脑缺氧/缺血损伤中的作用。本项目旨在了解AMPA/红藻氨酸对OLs损伤的发育特异性的基础，以及这是否可能是体内未成熟脑损伤的重要组成部分。项目4的总体假设是OLs对AMPA/红藻氨酸受体介导的兴奋性毒性的成熟依赖性脆弱性是未成熟脑白色物质中OL死亡的重要原因，因此是PVL发病机制中的潜在重要因素。 目标1.确定OLs对AMPA/红藻氨酸盐毒性的成熟依赖性脆弱性是否与体外和体内OLs中AMPA/红藻氨酸盐受体表达的发育差异有关。我们将建立AMPA/红藻氨酸受体的发展概况，主要是OL;目的2。描述AMPA/红藻氨酸受体介导的OL发育毒性的机制。我们将确定成熟的差异OL的脆弱性，并确定是否钙++内流和自由基介导的死亡发展OL在体外;目的3。确定在PVL的啮齿动物模型中由脑内注射AMPA/红藻氨酸激动剂诱导的白色损伤是否是成熟依赖性的;以及目的4。确定OLS对大鼠脑缺氧/缺血的成熟脆弱性和AMPA/红藻氨酸受体在该脆弱性中的作用，以及谷氨酸拮抗剂是否代表预防未成熟脑中缺氧-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。

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.