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

动物注射3-甲氧基羰基-2,2,5,5-四甲基吡啶-1-氧（PCAM），用微透析技术和ESR分析测量海马的一氧化氮自由基。测定抗氧化作用，监测谷氨酸转运蛋白抑制剂l -反式吡咯烷- 2,4 -二羧酸（L-trans PDC）和对照动物透析液中氮氧化物自由基信号幅度的顺序变化。结果表明，l -反式PDC组氮氧化物自由基的中位半衰期明显延长，呈指数衰减。我们对Fe^<+++>诱导的癫痫大鼠海马间期氧化还原状态和胱氨酸/谷氨酸交换器（xCT） mRNA表达进行了定性分析。与对照组相比，Fe^<+++>诱导大鼠同侧海马xCT mRNA表达降低。Fe^<+++>组一氧化氮自由基半衰期明显长于对照组。细胞外谷氨酸水平升高通过抑制谷氨酸转运活性而引起的氧化应激是由于转运体具有sh -氧化还原调节位点，易受内源性氧化剂的影响。xCT减少引起的胱氨酸摄取减少和细胞外谷氨酸增加导致抗氧化剂谷胱甘肽减少，从而降低抗氧化能力。我们得出结论，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。

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.