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Neuroprotective effects of a novel kynurenic acid analogue in a transgenic mouse model of Huntington’s disease

  • Basic Neurosciences, Genetics and Immunology - Original Article
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Abstract

Huntington’s disease (HD) is a progressive neurodegenerative disorder, the pathomechanism of which is not yet fully understood. Excitotoxicity is known to be involved in the development of HD and antiglutamatergic agents may, therefore, have beneficial neuroprotective effects. One of these agents is the tryptophan metabolite kynurenic acid (KYNA), which is an endogenous NMDA receptor antagonist. However, its pharmacological properties rule out its systemic administration in CNS disorders. We have tested a novel KYNA analogue, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride, in the N171-82Q transgenic mouse model of HD. The analogue exhibited several significant effects: it prolonged the survival of the transgenic mice, ameliorated their hypolocomotion, prevented the loss of weight and completely prevented the atrophy of the striatal neurons. The beneficial effects of this KYNA analogue are probably explained by its complex anti-excitotoxic activity. As it did not induce any appreciable side-effect at the protective dose applied in a chronic dosing regime in this mouse model, it appears worthy of further thorough investigations with a view to eventual clinical trials.

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Acknowledgments

This work was supported by grants ETT 026-04, NAP-BIO-06-BAYBIOSZ, TÁMOP-4.2.2-08/1/2008-0002, NIH (DA09158, NS030549) and OTKA (K75628). Gábor Nyiri was supported by János Bolyai Research Fellowship. We thank Andrea Varga and Gábor Patkovics for their technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Neurology, Albert Szent-Györgyi Clinical Centre, University of Szeged, Semmelweis u. 6, Szeged, 6725, Hungary

    Dénes Zádori, László Vécsei & Péter Klivényi

  2. Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony u. 43, Budapest, 1083, Hungary

    Gábor Nyiri, András Szőnyi & Tamás F. Freund

  3. Department of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, Szeged, 6720, Hungary

    István Szatmári & Ferenc Fülöp

  4. Department of Physiology, Anatomy and Neuroscience, University of Szeged, Közép fasor 52, Szeged, 6726, Hungary

    József Toldi

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  1. Dénes Zádori
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  2. Gábor Nyiri
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  3. András Szőnyi
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  4. István Szatmári
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  8. László Vécsei
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  9. Péter Klivényi
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Correspondence to Péter Klivényi.

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Zádori, D., Nyiri, G., Szőnyi, A. et al. Neuroprotective effects of a novel kynurenic acid analogue in a transgenic mouse model of Huntington’s disease. J Neural Transm 118, 865–875 (2011). https://doi.org/10.1007/s00702-010-0573-6

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  • DOI: https://doi.org/10.1007/s00702-010-0573-6

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