Dysfunction of cystine/glutamate antiporter system in the hippocampus of epileptic rats

癫痫大鼠海马胱氨酸/谷氨酸逆向转运蛋白系统功能障碍

• 批准号: 20591415
• 负责人: DOI Taku
• 金额: $ 2.83万
• 依托单位: University of Miyazaki
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20591415/
• 关键词: 医歯薬学; てんかん; グルタミン酸; 抗酸化能; レドックス; 酸化ストレス; cystine/glutamate transporter (xCT); cstine; glutamate transorterxCT; cystine; glutamate transporter(xCT)

Animals were injected 3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (PCAM) and the nitroxide radicals were measured with microdialysis technique and an ESR analysis in the hippocampus. The antioxidant effect was measured to monitor sequential changes in the signal amplitude of nitroxide radical in the dialysate of both glutamate transporter inhibitor L-trans-pyrrolidine-2, 4-dicarboxylic acid (L-trans PDC) and control animals. The pattern showed exponential decay with median half-life of the nitroxide radical took significantly longer in the L-trans PDC group. And we performed qualitative analysis of redox state and cystine/glutamate exchanger (xCT) mRNA expression in the interictal state in the hippocampus of Fe^<+++>-induced epileptic rats. The expression of xCT mRNA in the ipsilateral hippocampus of Fe^<+++>-induced rats was decreased compared with controls. The half-life of nitroxide radical in Fe^<+++> group was statistically longer than that of control. The oxidative stress induced by the increased extracellular glutamate level through the suppression of glutamate transport activity results from transporters having a SH-redox modulatory site that is vulnerable to endogenous oxidants. Less cystine uptake induced by reduced xCT and increased extracellular glutamate leads to diminish of antioxidant glutathione, as a result reduces anti-oxidant ability. We conclude that collapse of glutamate regulation and antioxidant ability may be fundamental to Fe^<+++>-induced epileptogenesis.

给动物注射3-甲氧羰基-2，2，5，5-四甲基吡咯烷-1-氧基（PCAM），用微透析技术和ESR分析测定海马内的氮氧自由基。测定谷氨酸转运体抑制剂L-trans-pyrrolidine-2，4-dicarboxylic acid（L-transPDC）和对照动物透析液中的抗氧化作用以监测氮氧自由基信号幅度的顺序变化。该模式显示指数衰减，在L-反式PDC组中，氮氧自由基的中位半衰期显著更长。并对Fe^<+>致痫大鼠发作间期海马氧化还原状态和胱氨酸/谷氨酸交换体（cystine/glutamate exchange，xCT）mRNA表达进行了定性分析。与对照组相比，Fe^<+>诱导的大鼠同侧海马中xCT mRNA的表达降低。Fe^<+>组氮氧自由基半衰期明显长于对照组。通过抑制谷氨酸转运活性而增加的细胞外谷氨酸水平诱导的氧化应激来自具有SH-氧化还原调节位点的转运蛋白，该位点易受内源性氧化剂的影响。减少的xCT和增加的细胞外谷氨酸诱导的胱氨酸摄取减少导致抗氧化剂谷胱甘肽减少，从而降低抗氧化能力。我们的结论是谷氨酸调节和抗氧化能力的崩溃可能是Fe^<+>诱导癫痫发生的基础。

项目成果

Differential molecular regulation of glutamate in kindling resistant rats

• DOI: 10.1016/j.brainres.2010.11.085
• 发表时间: 2011-02-23
• 期刊: BRAIN RESEARCH
• 影响因子: 2.9
• 作者: Doi, Taku;Ueda, Yuto;Willmore, L. James
• 通讯作者: Willmore, L. James

PTZによるキンドリング完成群と非完成群におけるグリア型グルタミン酸トランスポーターの発現比較

PTZ介导的点燃完成组与非完成组胶质细胞谷氨酸转运蛋白表达比较

• 发表时间: 2008
• 作者: 土井拓;植田勇人;高木麻夕子
• 通讯作者: 高木麻夕子

Levetiracetam enhances endogenous antioxidant in the hippocampus of rats: In vivo evaluation by brain microdialysis combined with ESR spectroscopy

• DOI: 10.1016/j.brainres.2009.02.040
• 发表时间: 2009-04
• 期刊: Brain Research
• 影响因子: 2.9
• 作者: Y. Ueda;Taku Doi;Mayuko Takaki;Keiko Nagatomo;A. Nakajima;L. James Willmore

ウイルモアジェームス、NMDA誘発性痙攣に伴うグルタミン酸、GABAの遊離動態パターンの相違

Wilmore James，与 NMDA 诱导的惊厥相关的谷氨酸和 GABA 释放动力学模式的差异

• 发表时间: 2009
• 作者: 千原悠里;植田勇人;土井拓
• 通讯作者: 土井拓

Increased endoplasmis reticulum Stress in the amygdaloid kindling model of rats

大鼠杏仁核点火模型中内质网应激增加

• 发表时间: 2010
• 作者: Yuto Ueda;Y.Chihara;T.Doi;J.Willmore
• 通讯作者: J.Willmore