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Molecular Pharmacology

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Research ArticleArticle

Robust Protective Effects of a Novel Multimodal Neuroprotectant Oxopropanoyloxy Benzoic Acid (a Salicylic Acid/Pyruvate Ester) in the Postischemic Brain

Seung-Woo Kim, Hyun Ji Kim, Joo-Hyun Shin, Il-Doo Kim, Jung-Eun Lee, Pyung-Lim Han, Sung-Hwa Yoon and Ja-Kyeong Lee
Molecular Pharmacology February 2011, 79 (2) 220-228; DOI: https://doi.org/10.1124/mol.110.067520
Seung-Woo Kim
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Hyun Ji Kim
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Joo-Hyun Shin
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Il-Doo Kim
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Jung-Eun Lee
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Pyung-Lim Han
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Sung-Hwa Yoon
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Ja-Kyeong Lee
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Abstract

Cerebral ischemia leads to brain injury via a complex series of pathophysiological events. Therefore, multidrug treatments or multitargeting drug treatments are attractive options in efficiently limiting brain damage. Here, we report a novel multifunctional compound oxopropanoyloxy benzoic acid (OBA-09), a simple ester of pyruvate and salicylic acid. This protective effect was manifested by recoveries from neurological and behavioral deficits. OBA-09 exhibited antioxidative effects in the postischemic brain, which was evidenced by remarkable reduction of lipid peroxidation and 4-hydroxy-2-nonenal staining in OBA-09-administered animals. Reactive oxygen species generation was markedly suppressed in primary cortical cultures under oxygen-glucose deprivation. More interestingly, OBA-09 was capable of scavenging hydroxyl radical in cell-free assays. High-performance liquid chromatography results demonstrated that OBA-09 was hydrolyzed to salicylic acid and pyruvate with t1/2 = 43 min in serum and 4.2 h in brain parenchyma, indicating that antioxidative function of OBA-09 is executed by itself and also by salicylic acid after the hydrolysis. In addition to antioxidative function, OBA-09 exerts anti-excitotoxic and anti-Zn2+-toxic functions, which might be attributed to attenuation of ATP and nicotinamide adenine dinucleotide depletion and to the suppression of nuclear factor-κB activity induction. Together these results indicate that OBA-09 has a potent therapeutic potential as a multimodal neuroprotectant in the postischemic brain and these effects were conferred by OBA-09 itself and subsequently its hydrolyzed products.

Footnotes

  • This work was supported by the Health Planning Technology and Evaluation Board [Translational Research Grant R05-003000-10562-0].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.067520.

  • ABBREVIATIONS:

    OBA-09
    oxopropanoyloxy benzoic acid
    HPLC
    high-performance liquid chromatography
    ROS
    reactive oxygen species
    HNE
    4-hydroxy-2-nonenal
    MCAO
    middle cerebral artery occlusion
    mNSS
    modified neurological severity score
    TTC
    2,3,5-triphenyl tetrazolium chloride
    MEM
    minimum essential medium
    DIV
    days in vitro
    OGD
    oxygen-glucose deprivation
    EBSS
    Earle's balanced salt solution
    DCF
    5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate
    MTT
    3-[4,5-dimethylthiazol-2-yo]-2,5-diphenyltetrazolium bromide
    MDA
    malondialdehyde
    NF-κB
    nuclear factor-κB
    ESI
    electrospray ionization
    MS
    mass spectrometry
    LC
    liquid chromatography
    NMDA
    N-methyl-d-aspartate.

  • Received August 1, 2010.
  • Accepted October 28, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (2)
Molecular Pharmacology
Vol. 79, Issue 2
1 Feb 2011
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Research ArticleArticle

Robust Protective Effects of a Novel Multimodal Neuroprotectant Oxopropanoyloxy Benzoic Acid (a Salicylic Acid/Pyruvate Ester) in the Postischemic Brain

Seung-Woo Kim, Hyun Ji Kim, Joo-Hyun Shin, Il-Doo Kim, Jung-Eun Lee, Pyung-Lim Han, Sung-Hwa Yoon and Ja-Kyeong Lee
Molecular Pharmacology February 1, 2011, 79 (2) 220-228; DOI: https://doi.org/10.1124/mol.110.067520

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Research ArticleArticle

Robust Protective Effects of a Novel Multimodal Neuroprotectant Oxopropanoyloxy Benzoic Acid (a Salicylic Acid/Pyruvate Ester) in the Postischemic Brain

Seung-Woo Kim, Hyun Ji Kim, Joo-Hyun Shin, Il-Doo Kim, Jung-Eun Lee, Pyung-Lim Han, Sung-Hwa Yoon and Ja-Kyeong Lee
Molecular Pharmacology February 1, 2011, 79 (2) 220-228; DOI: https://doi.org/10.1124/mol.110.067520
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