Levetiracetam enhances endogenous antioxidant in the hippocampus of rats: In vivo evaluation by brain microdialysis combined with ESR spectroscopy
Levetiracetam enhances endogenous antioxidant in the hippocampus of rats: In vivo evaluation by brain microdialysis combined with ESR spectroscopy
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DOI：
10.1016/j.brainres.2009.02.040
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发表时间：
2009-04
期刊：
影响因子：
2.9
通讯作者：
Y. Ueda;Taku Doi;Mayuko Takaki;Keiko Nagatomo;A. Nakajima;L. James Willmore
中科院分区：
文献类型：
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作者：
Y. Ueda;Taku Doi;Mayuko Takaki;Keiko Nagatomo;A. Nakajima;L. James Willmore
我们试图通过测量左乙拉西坦（LEV）在自由活动状态下大鼠海马体内的抗氧化作用来探索其神经保护效果。采用雄性 Wistar 大鼠，通过微透析结合电子自旋共振光谱法评估 LEV 的体内抗氧化作用。使用系统施用的血脑屏障渗透性硝基氧自由基（PCAM）以指数衰减方式减少的原理来检查抗氧化效果，该衰减方式与大脑中的抗氧化剂的量相关。将正常林格氏溶液灌注期间的 PCAM 衰减率与 32 μM 和 100 μM LEV 共灌注期间的 PCAM 衰减率进行比较。检查了体内抗氧化作用。此外，在腹腔注射 54 毫克/天剂量的 LEV 14 天后，测量了大鼠海马中与氧化还原调节相关的胱氨酸/谷氨酸交换器 (xCT) 和诱导型一氧化氮合酶 (iNOS) 蛋白的表达。与对照实验的结果相比，LEV灌注后PCAM的半衰期在统计学上缩短。虽然促氧化蛋白 iNOS 的表达降低，但抗氧化蛋白 xCT 的表达在 LEV 的作用下显着增加。 xCT的作用是将谷胱甘肽的内部物质胱氨酸转运到细胞内。 LEV 与增加的 xCT 和减少的 iNOS 表达共灌注导致硝基氧自由基的半衰期缩短，揭示了内源性抗氧化作用或自由基清除活性的增强。这项研究的结果表明，LEV 与抗坏血酸和 α-生育酚协同增强海马的基础内源性抗氧化作用。我们的研究结果进一步表明，LEV 通过以下方式发挥神经保护作用：1）改变与脂质过氧化相关的 xCT 和 iNOS 的表达，2）协同增强海马基础内源性抗氧化能力，3）降低谷氨酸的基础浓度，然后上调胱氨酸（GSH 的内部物质）的摄入量。
We have attempted to explore the neuroprotective effectiveness of levetiracetam (LEV) by measuring its in vivo antioxidant effect in the hippocampus of rats in a freely moving state. Male Wistar rats were used for the estimation of the in vivo antioxidant effect of LEV through microdialysis combined with electron spin resonance spectroscopy. The antioxidant effect was examined using the principle by which a systemically administered blood–brain barrier-permeable nitroxide radical (PCAM) decreases in an exponential decay manner that is correlated with the amount of antioxidant in the brain. The PCAM decay ratio during perfusion with normal Ringer's solution was compared with that during 32 μM and 100 μM LEV co-perfusion. The in vivo antioxidant effect was examined. In addition, the expressions of the cystine/glutamate exchanger (xCT) and the inducible nitric oxide synthase (iNOS) protein related to redox regulation were measured in the hippocampus of rats after 14 days of administration of LEV at a dose of 54 mg/day i.p. The half-life of PCAM was statistically shortened after LEV perfusion compared with the results of the control experiment. While the expression of the pro-oxidant protein iNOS was decreased, that of the antioxidant protein xCT was statistically increased by the administration of LEV. The role of xCT is to transport cystine, the internal material of glutathione, into the cell. The shortened half-life of the nitroxide radical by co-perfusion of LEV with increased xCT and decreased iNOS expression revealed the enhancement of the endogenous antioxidant effect or free-radical scavenging activity. The results of this study suggest that LEV synergistically enhances the basal endogenous antioxidant effect in the hippocampus with ascorbic acid and α-tocopherol. Our findings further suggest that LEV exerts a neuroprotective role by 1) modifying the expression of xCT and iNOS in connection with lipid peroxidation, 2) synergistically enhancing the increased basal endogenous antioxidant ability in the hippocampus, and 3) decreasing the basal concentration of glutamate followed by up-regulation of the intake of cystine, an internal material of GSH.