Effect of extracellure concentration in post ischemic glutamate reuptake, depend on brain temperature and drug.

细胞外浓度对缺血后谷氨酸再摄取的影响取决于脑温度和药物。

基本信息

批准号：
11680766
负责人：
ASAI Satoshi
金额：
$ 2.3万
依托单位：
Nihon University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

Recently, we reported the application of an oxygen-independent real-time technique for monitoring glutamate levels in the extracellular space during in vivo ischemia and hypoxia, using a dialysis electrode. This dialysis electrode technique allows detailed analysis of the in vivo dynamics of not only severe acute ischemia produced by transecting the bilateral carotid arteries, but also those of an ischemia-reperfusion model. In particular, during the ischemia-reperfusion period, the mechanisms of glutamate release are assumed to involve three sequential processes : 1) neurotransmitter, i.e.glutamate, release from synaptic vesicles (1st phase of [Glu]_e), 2) reversed uptake of glutamate from the metabolic pool in neuronal cells (2nd phase of release), and 3) re-uptake into the intracellular space by normalization of the glutamate uptake carrier system during the postischemic period (re-uptake phase of [Glu]_e).We found that the in vivo dynamics of biphasic [Glu]_e output from the intrac … More ellular space, as well as reduced reuptake of [Glu]_e into the intracellular space following 10 minutes of ischemia in terms of the three above-mentioned [Glu]_e compartments, and that an ischemic injury mechanism which is sensitive to temperature may not actually increase the extracellular glutamate concentration ([Glu]_e) during the intraischemic period, but rather impairs the Glu re-uptake system, which has been suggested to be involved in the reversed uptake of glutamate. We speculated that enhancing Glu re-uptake, pharmacologically or hypothermically, may shorten exposure to high [Glu]_e in the postischemic period and thereby decrease its deleterious excitotoxic effect on neuronal cells.Preloading with a novel glutamate transporter inhibitor (tPDC) decreased both the 1st and 2nd phases of [Glu]e evation. Furthermore, rats treated with nicergoline (32 mg /kg, i.p.), an ergot alkaloid derivative, showed minimal mhibition of the [Glu]_e elevation which characteristically occurs during the 10-min intraischemic period, while Glu re-uptake was dramatically improved in the postischemic period, when severe transient global ischemia was caused by mild hyperthennia. Moreover, the nicergoline (32 mg /kg, i.p.) treated rats showed reduced cell death morphologically and clearly had a far lower mortality. The present study suggests that the development of therapeutic strategies aimed at inhibition or prevention of the reversed uptake of glutamate release during ischemia, i.e. activation of the glutamate uptake mechanism, is a promising approach to reduce neural damage occurring in response to brain ischemia. Less

最近，我们报道了应用不依赖于氧气的实时技术来监测体内缺血和缺氧期间细胞外空间的谷氨酸水平，该透析电极技术不仅可以详细分析体内动力学。横断双侧颈动脉产生的严重急性缺血，以及缺血再灌注模型的模型，特别是在缺血再灌注期间，谷氨酸释放的机制。假设涉及三个连续过程：1）神经递质，即谷氨酸，从突触小泡中释放（[Glu]_e的第一阶段），2）从神经元细胞的代谢池中反向摄取谷氨酸（释放的第二阶段），以及3）在缺血后时期（再摄取阶段）通过谷氨酸摄取载体系统的正常化重新摄取到细胞内空间[Glu]_e)。我们发现，从细胞内空间输出双相 [Glu]_e 的体内动力学，以及缺血 10 分钟后 [Glu]_e 重新摄取到细胞内空间的减少上述三个[Glu]_e区室，并且对温度敏感的缺血性损伤机制实际上可能不会增加细胞外谷氨酸浓度（[Glu]_e）在缺血期间，反而会损害谷氨酸再摄取系统，该系统被认为参与了谷氨酸的逆转摄取。我们推测，通过药理学或低温方式增强谷氨酸再摄取，可能会缩短暴露于高[Glu]的时间。 _e 在缺血后时期，从而减少其对神经元细胞的有害兴奋毒性作用。预加载新型谷氨酸转运蛋白抑制剂 (tPDC) 降低了[Glu]e 升高的第一阶段和第二阶段此外，给予麦角林（32mg/kg，腹腔注射）（一种麦角生物碱衍生物）的大鼠表现出对 [Glu]e 升高的最小抑制，其典型地发生在10分钟缺血期间。，而在缺血后时期，当轻微的高温引起严重的短暂性全身缺血时，谷氨酸的再摄取显着改善。尼麦角林（32 mg/kg，腹膜内注射）治疗的大鼠在形态上表现出细胞死亡减少，并且死亡率明显降低。本研究表明，开发旨在抑制或预防缺血期间谷氨酸释放的逆转摄取的治疗策略。激活谷氨酸摄取机制是减少脑缺血引起的神经损伤的一种有前途的方法。