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Mitochondrial disturbances, excitotoxicity, neuroinflammation and kynurenines: Novel therapeutic strategies for neurodegenerative disorders

  • Dénes Zádori
    Affiliations
    Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary
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  • Péter Klivényi
    Affiliations
    Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary
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  • Levente Szalárdy
    Affiliations
    Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary
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  • Ferenc Fülöp
    Affiliations
    Institute of Pharmaceutical Chemistry and Research Group of Stereochemistry, Hungarian Academy of Sciences, Faculty of Pharmacy, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary
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  • József Toldi
    Affiliations
    Department of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary

    Neuroscience Research Group of the Hungarian Academy of Sciences and the University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary
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  • László Vécsei
    Correspondence
    Corresponding author at: Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary. Tel.:+36 62 545351; fax: +36 62 545597.
    Affiliations
    Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary

    Neuroscience Research Group of the Hungarian Academy of Sciences and the University of Szeged, Semmelweis u. 6, H-6725 Szeged, Hungary
    Search for articles by this author

      Abstract

      A mitochondrial dysfunction causes an abatement in ATP production, the induction of oxidative damage and the propagation of cell death pathways. It is additionally closely related to both glutamate excitotoxicity and neuroinflammation. All of these interconnected aspects of a cellular dysfunction are involved in the pathogenesis of numerous neurological disorders, including those with an acute (e.g. ischemic stroke) or a chronic (e.g. Huntington's disease) onset. Both acute and chronic neurodegenerative disorders have been demonstrated to involve multiple imbalances of the kynurenine pathway metabolism in the pathogenesis of the disease. As regards neuroactive compounds featuring in the pathway, quinolinic acid is a specific agonist of N-methyl-d-aspartate receptors, and a potent neurotoxin with additional and marked free radical-producing and lipid peroxidation-inducing properties. The toxic effects of 3-hydroxy-L-kynurenine are mediated by free radicals. Besides the possibility of increasing brain kynurenic acid concentrations, L-kynurenine may have vasoactive properties, too. Kynurenic acid has proven to be neuroprotective in several experimental settings, but in consequence of its pharmacokinetic properties it is not applicable as systemic administration in human cases. The aim of this short review is to emphasize the common features of cerebral ischemia and Huntington's disease and to highlight therapeutic strategies targeting the kynurenine pathway.

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