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

Abstract

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 microM and 100 microM 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 alpha-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.

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  • Publisher Full Text
  • Authors

    Ueda Y, Doi T, Takaki M, Nagatomo K, Nakajima A, Willmore LJ

    Institution

    Section of Psychiatry, Department of Clinical Neuroscience, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan. usan@med.miyazaki-u.ac.jp

    Source

    Brain research 1266: 2009 Apr 17 pg 1-7

    MeSH

    Amino Acid Transport System y+
    Amino Acids
    Animals
    Antioxidants
    Ascorbic Acid
    Blotting, Western
    Electron Spin Resonance Spectroscopy
    Hippocampus
    Male
    Microdialysis
    Neuroprotective Agents
    Nitric Oxide Synthase Type II
    Nitrogen Oxides
    Piracetam
    Rats
    Rats, Wistar
    alpha-Tocopherol

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    19268434