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。

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11680766/
• 关键词: dialysis electrode; brain ischemia; glutamate; glutamate uptake; hypothermia; glutamate transporter; Nicergoline; t-PDC; 透析酸素電極; 脳保護薬

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，我们报道了一种不依赖于氧的实时技术，用于监测在体内缺血和缺氧期间细胞外间隙中的谷氨酸水平，使用透析电极的应用。这种透析电极技术不仅可以详细分析通过横断双侧颈动脉产生的严重急性缺血的体内动力学，而且可以详细分析缺血-再灌注模型的体内动力学。特别地，在缺血-再灌注期间，谷氨酸释放的机制被认为涉及三个连续过程：1）神经递质，即谷氨酸，从突触囊泡释放（第1相[Glu]_e）; 2）神经元细胞从代谢池中反向摄取谷氨酸（第二阶段释放），和3）在缺血后期间通过谷氨酸摄取载体系统的正常化而再摄取到细胞内空间中我们发现，在体内，[Glu]_e的双相输出动力学与[Glu]_e的再摄取相有关，而[Glu]_e的再摄取相则与[Glu]_e的再摄取相有关。 ...更多信息 细胞间隙，以及根据上述三个[Glu]_e隔室，缺血10分钟后[Glu]_e进入细胞内间隙的再摄取减少，并且对温度敏感的缺血损伤机制实际上可能不会增加缺血期间的细胞外谷氨酸浓度（[Glu]_e），而是损害Glu再摄取系统，它被认为与谷氨酸的反向摄取有关。我们推测，在低温或低温条件下，增强Glu再摄取可能缩短缺血后高[Glu]_e暴露时间，从而降低其对神经细胞的有害兴奋毒性作用，预先给予一种新的谷氨酸转运体抑制剂（tPDC）可减少[Glu]_e的第1和第2时相释放。此外，用尼麦角林（32 mg /kg，i. p.），麦角生物碱衍生物的[Glu]_e的升高在缺血10分钟内表现出最小的抑制作用，而Glu的再摄取在缺血后阶段显著改善，当严重的短暂性全脑缺血由轻度的hypothennia引起时。此外，尼麦角林（32 mg /kg，i. p.）经处理的大鼠在形态学上表现出减少的细胞死亡，并且明显具有低得多的死亡率。目前的研究表明，发展的治疗策略，旨在抑制或预防缺血过程中谷氨酸释放的逆转摄取，即激活谷氨酸摄取机制，是一种有前途的方法，以减少神经损伤发生在脑缺血反应。少

项目成果

Satoshi Asai, et al.: "Oxygen-independent real-time monitoring of distinct biphasic glutamate release using dialysis electrode in rat striatum during anoxia - in vivo evaluation of glutamate releasse and reversed uptak."Journal of Neurotrauma. 17. 1105-11

Satoshi Asai 等人：“缺氧期间使用透析电极对大鼠纹状体中不同双相谷氨酸释放进行不依赖于氧气的实时监测 - 谷氨酸释放和逆转摄取的体内评估。”神经创伤杂志。

Satoshi Asai, et al.: "Nicergoline enhances glutamate re-uptake and protects against brain damage in rat global brain ischemia."Europian Journal of Pharmacology. 383. 267-274 (1999)

Satoshi Asai 等人：“尼麦角林增强谷氨酸的再摄取，并防止大鼠全脑缺血的脑损伤。”《欧洲药理学杂志》。

Sugahara, M., Asai, S., Zhao, H., Nagata, T., Kunimatsua, T., Ishii, Y., Kohno, T.and Ishikawa, K.: "Extracellular glutamate changes in rat striatum during ischemia determined by a novel dialysis electrode and conventional microdialysis."Neurochemistry In

Sugahara, M.、Asai, S.、Zhao, H.、Nagata, T.、Kunimatsua, T.、Ishii, Y.、Kohno, T. 和 Ishikawa, K.：“确定缺血期间大鼠纹状体的细胞外谷氨酸变化

Satoshi Asai, et al.: "Two distinct components of initial glutamate release synchronized with anoxic depolarization in rat global brain ischemia."Neuroreport. 11. 2947-2952 (2000)

Satoshi Asai 等人：“在大鼠全脑缺血中，初始谷氨酸释放的两种不同成分与缺氧去极化同步。”Neuroreport。

Asai, S., Zhao, H., Kohno, T., Takahashi, Y., Nagata, T.and Ishikawa, K.: "Quantitative evaluation of extracellure glutamate concentration in postischemic glutamate re-uptake, dependent on brain temperature, in the rat following severe global brain ischem

Asai, S.、Zhao, H.、Kohno, T.、Takahashi, Y.、Nagata, T. 和 Ishikawa, K.：“对缺血后谷氨酸再摄取中细胞外谷氨酸浓度的定量评估，取决于脑温度，