CONTRIBUTION OF AMPA/KA RECEPTOR TO HYPOXIC NEURONAL INJURY IN VITRO

AMPA/KA 受体对体外缺氧神经元损伤的作用

• 批准号: 6112508
• 负责人: Dennis W Choi
• 金额: $ 14.01万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6112508
• 关键词: NMDA receptors; calcium channel; cell death; cerebral ischemia /hypoxia; cobalt; excitatory aminoacid; glutamate receptor; in situ hybridization; inhibitor /antagonist; kainate; laboratory mouse; neurotoxins; polymerase chain reaction; receptor expression; single cell analysis; tissue /cell culture; voltage /patch clamp

Recent evidence has suggested that alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionate/kainate (AMPA/KA) type glutamate receptors may contribute importantly to brain damage following hypoxic-ischemic insults in vivo. The proposed experiments will utilize the simplified model system of cortical cell cultures exposed to oxygen-glucose deprivation to address three aspects of this contribution: 1) the contribution of AMPA/KA receptor-mediated injury to overall hypoxic neuronal death, and the relationship between this AMPA/KA receptor-mediated injury and hypoxic NMDA receptor-mediated injury; 2) the role of AMPA/KA receptors in mediating the hypoxia-induced death specifically of a newly=discovered cortical neuronal subpopulation, that likely expresses large numbers of AMPA/KA receptor-gated Ca2+ channels, and hence may be especially vulnerable to AMPA/KA receptor-mediated injury; and 3) the effect of sublethal oxygen-glucose deprivation on the subsequent neuronal expression of GluR-2 mRNA and functional AMPA/KA receptor-gated Ca2+ channels. These studies should yield novel information about the way AMPA/KA receptors may mediate hypoxic neuronal death, which may prove valuable in guiding the developing of effective therapeutic strategies aimed at reducing this form of injury in disease settings such as stroke or cardiac arrest.

最近的证据表明 α-氨基-3-羟基-5-甲基-4- 丙酸异恶唑/红藻氨酸 (AMPA/KA) 型谷氨酸受体可能 对缺氧缺血性损伤后的脑损伤有重要影响 体内。 所提出的实验将利用简化模型 暴露于氧-葡萄糖剥夺的皮质细胞培养系统 解决此贡献的三个方面：1） AMPA/KA 受体介导的损伤导致神经元整体缺氧死亡，以及 AMPA/KA 受体介导的损伤与 缺氧 NMDA 受体介导的损伤； 2）AMPA/KA受体的作用 介导缺氧引起的死亡，特别是新发现的 皮质神经元亚群，可能表达大量 AMPA/KA 受体门控 Ca2+ 通道，因此可能特别重要 易受 AMPA/KA 受体介导的损伤； 3）效果 亚致死氧-葡萄糖剥夺对随后神经元的影响 GluR-2 mRNA 和功能性 AMPA/KA 受体门控 Ca2+ 的表达 渠道。 这些研究应该会产生关于 AMPA/KA 方式的新信息 受体可能介导缺氧神经元死亡，这可能被证明是有价值的 指导制定有效的治疗策略 在中风或中风等疾病中减少这种形式的伤害 心脏停搏。