首页> 美国卫生研究院文献>other >Intrathecal infusion of a Ca2+ permeable AMPA channel blocker slows loss of both motor neurons and of the astrocyte glutamate transporter GLT-1 in a mutant SOD1 rat model of ALS
【2h】

Intrathecal infusion of a Ca2+ permeable AMPA channel blocker slows loss of both motor neurons and of the astrocyte glutamate transporter GLT-1 in a mutant SOD1 rat model of ALS

机译:鞘内注射Ca2 +渗透性AMPA通道阻滞剂可减缓ALS突变型SOD1大鼠模型中运动神经元和星形胶质细胞谷氨酸转运蛋白GLT-1的损失

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务,本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文,但由于OA文献来源多样且变更频繁,仍可能出现获取不到、文献不完整或与标题不符等情况,如果获取不到我们将提供退款服务。请知悉。

摘要

Elevated extracellular glutamate, resulting from a loss of astrocytic glutamate transport capacity, may contribute to excitotoxic motor neuron (MN) damage in ALS. Accounting for their high excitotoxic vulnerability, MNs possess large numbers of unusual Ca2+ permeable AMPA channels (Ca-AMPA channels), the activation of which triggers mitochondrial Ca2+ overload and strong reactive oxygen species (ROS) generation. However, the causes of the astrocytic glutamate transport loss remain unexplained. To assess the role of Ca-AMPA channels on the evolution of pathology in vivo, we have examined effects of prolonged intrathecal infusion of the Ca-AMPA channel blocker, 1-naphthyl acetylspermine (NAS), in G93A transgenic rat models of ALS. In wild type animals, immunoreactivity for the astrocytic glutamate transporter, GLT-1, was particularly strong around ventral horn MNs. However, a marked loss of ventral horn GLT-1 was observed, along with substantial MN damage, prior to onset of symptoms (90-100 d) in the G93A rats. Conversely, labeling with the oxidative marker, nitrotyrosine, was increased in the neuropil surrounding MNs in the transgenic animals. Compared to sham treated G93A animals, 30 day NAS infusions (starting at 67±2 days of age) markedly diminished the loss of both MNs and of astrocytic GLT-1 labeling. These observations are compatible with the hypothesis that activation of Ca-AMPA channels on MNs contributes, likely in part through oxidative mechanisms, to loss of glutamate transporter in surrounding astrocytes.
机译:由于星形细胞谷氨酸转运能力的丧失而导致的细胞外谷氨酸升高,可能导致ALS中的兴奋性运动神经元(MN)受损。考虑到其高度的兴奋毒性脆弱性,MN具有大量异常的Ca 2 + 渗透性AMPA通道(Ca-AMPA通道),其激活会触发线粒体Ca 2 + 过载以及强大的活性氧(ROS)生成。但是,尚无法解释造成星形细胞谷氨酸转运损失的原因。为了评估Ca-AMPA通道在体内病理学演变中的作用,我们在ALS的G93A转基因大鼠模型中检查了鞘内长时间输注Ca-AMPA通道阻滞剂1-萘乙酰精胺(NAS)的作用。在野生型动物中,星形胶质谷氨酸转运蛋白GLT-1的免疫反应性在腹角MN周围特别强。然而,在G93A大鼠出现症状之前(90-100 d),观察到腹角GLT-1明显丧失,并伴有大量MN损伤。相反,在转基因动物的MN周围的神经细胞中,用氧化标记硝基酪氨酸标记的现象增加了。与经假手术处理的G93A动物相比,NAS输注30天(从67±2天开始)显着减少了MN和星形胶质细胞GLT-1标记的损失。这些观察结果与以下假设相吻合:MNs上的Ca-AMPA通道激活可能部分地通过氧化机制导致了周围星形胶质细胞中谷氨酸转运蛋白的损失。

著录项

相似文献

  • 外文文献
  • 专利
代理获取

客服邮箱:kefu@zhangqiaokeyan.com

京公网安备:11010802029741号 ICP备案号:京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有
  • 客服微信

  • 服务号