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Pre-treatment with new kynurenic acid amide dose-dependently prevents the nitroglycerine-induced neuronal activation and sensitization in cervical part of trigemino-cervical complex

  • Neurology and Preclinical Neurological Studies - Original Article
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Abstract

The systemic administration of nitroglycerine induces attacks in migraineurs and is able to activate and sensitize the trigeminal system in animals involving glutamate and α7-nicotinic acetylcholine receptors, among others. Kynurenic acid is one of the endogenous glutamate receptor antagonists, and exerts inhibitory action on the α7-nicotinic acetylcholine receptors. Since kynurenic acid penetrates the blood–brain barrier poorly, therefore a newly synthesized kynurenic acid amide, N-(2-N-pyrrolidinylethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KYNAa) was used with such a side-chain substitution to facilitate brain penetration in our study. We evaluated its modulatory effect on kynurenic acid concentration in the cervical part of trigemino-cervical complex (C1–C2) and in the model of nitroglycerine-induced trigeminal activation using male Sprague–Dawley rats. One hour after 1 mmol/kg bodyweight KYNAa administration, the kynurenic acid level increased significantly in C1–C2, which returned to the basal level at 300 min measured by high-performance liquid chromatography. KYNAa pre-treatment had dose-dependent, mitigating action on nitroglycerine-induced decrease in calcitonin gene-related peptide and increase in c-Fos, neuronal nitric oxide synthase and calmodulin-dependent protein kinase II alpha expression in the C1–C2. KYNAa also mitigated the behavioural changes after nitroglycerine. Thus, in this model KYNAa is able to modulate in a dose-dependent manner the changes in neurochemical markers of activation and sensitization of the trigeminal system directly and indirectly—via forming kynurenic acid, possibly acting on peripheral and central glutamate or α7-nicotinic acetylcholine receptors. These results suggest that application of kynurenic acid derivatives could be a useful therapeutic strategy in migraine headache in the future with a different mechanism of action.

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Acknowledgments

This work was supported by OTKA KI05077, TÁMOP-4.2.2.A-11/1/KONV-2012-0052 and the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of TÁMOP 4.2.4.A/2-11-1-2012-0001 “National Excellence Program”. Dr. Árpád Párdutz was supported by the Bolyai Scholarship Programme of the Hungarian Academy of Sciences. We acknowledge Mrs. Valéria Vékony for the histotechnical assistance, Péter Klivényi and István Ilisz for their valuable technical advices and David Durham for the linguistic correction of the manuscript.

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

    Annamária Fejes-Szabó, Zsuzsanna Bohár, Enikő Vámos, Gábor Nagy-Grócz, Lilla Tar, Gábor Veres, Dénes Zádori, Márton Szentirmai, János Tajti, Árpád Párdutz & László Vécsei

  2. Neuroscience Research Group of the Hungarian Academy of Sciences and University of Szeged, Szeged, Hungary

    Zsuzsanna Bohár & László Vécsei

  3. Institute of Pharmaceutical Chemistry and Stereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, Szeged, Hungary

    István Szatmári & Ferenc Fülöp

  4. Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

    József Toldi

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  1. Annamária Fejes-Szabó
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Correspondence to László Vécsei.

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Á. Párdutz, L. Vécsei contributed equally to this work.

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Fejes-Szabó, A., Bohár, Z., Vámos, E. et al. Pre-treatment with new kynurenic acid amide dose-dependently prevents the nitroglycerine-induced neuronal activation and sensitization in cervical part of trigemino-cervical complex. J Neural Transm 121, 725–738 (2014). https://doi.org/10.1007/s00702-013-1146-2

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